Is PAH p.Arg413Pro (c.1238G>C) pathogenic?

PAH p.Arg413Pro (c.1238G>C) is classified Pathogenic in PAH (ClinVar, Expert panel, 12 submitters; last evaluated 2018-08-05). AlphaMissense: likely pathogenic (0.9812); Ultra-rare (popmax 0.0267%, eas); Associated with phenylketonuria.

What condition is associated with PAH p.Arg413Pro (c.1238G>C)?

PAH p.Arg413Pro (c.1238G>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Arg413Pro (c.1238G>C) in the general population?

PAH p.Arg413Pro (c.1238G>C) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

How is Phenylketonuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PAH p.Arg413Pro (c.1238G>C)?

AlphaMissense predicts likely pathogenic (score 0.9812) — an in-silico prediction, not a clinical call.

PAH p.Arg413Pro

c.1238G>C · rs79931499 · VCV592

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

AlphaMissense

likely pathogenic

0.9812 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4_Moderate PS3 PP3 PM3

Curation rationale (ClinGen, verbatim)

PAH-specific ACMG/AMP criteria applied: PS3: In vitro expression of altered protein in COS cells produces severe decrease of PAH activity (<3%); PM2: Extremely low frequency. ExAC MAF=0.00012; PP4_Moderate: Detected in PKU patients, BH4 deficiency excluded; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.895; PM3: Detected with V388M (pathogenic) in 2 patients (PMID:9860305; PMID:21307867). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PS3, PM2, PP4_Moderate, PP3, PM3).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9812	likely pathogenic ✓ concordant with ClinVar · top 9% in PAH
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -14.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.49	GERP -4.4
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	18.58	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% East Asian · 12/44,876 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00143% 23/1,613,846 alleles · ultra-rare exomes 23/1,461,692 · genomes 0/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.000848%	117,986

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PAH
Protein: p.Arg413Pro
Coding: c.1238G>C
MANE Select: NM_000277
dbSNP: rs79931499
Type: single nucleotide variant
Location: chr12:102840477 (GRCh38)
Gene constraint: LOEUF 1.265 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.04 · 21 PDB
Residue 413: a UniProt-annotated variant site (in pah deficiency); a UniProt-annotated variant site (in pah deficiency; severe); a β-strand

Full PAH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

phenylketonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Phenylketonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (France)

Similar variants

PAH p.Arg413Ser Pathogenic ★★★ ⚠ same residue
PAH p.Arg413Cys Uncertain significance ★★★ ⚠ same residue
PAH p.Arg413Gly Uncertain significance ★★★ ⚠ same residue
PAH p.Arg413His Pathogenic/Likely pathogenic ★★ ⚠ same residue
PAH p.Arg413_Tyr414delinsProCys Pathogenic ★ same residue
PAH c.1065+1G>A Likely pathogenic ★★★ same condition
PAH c.1065+1G>T Likely pathogenic ★★★ same condition
PAH c.1065+3A>G Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pah-p-arg413pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown