Is PAH p.Arg71Pro (c.212G>C) pathogenic?

PAH p.Arg71Pro (c.212G>C) is classified Uncertain significance in PAH (ClinVar, Expert panel, 2 submitters; last evaluated 2026-06-17). AlphaMissense: ambiguous (0.3977); Absent from gnomAD v4.1; Associated with phenylketonuria.

What condition is associated with PAH p.Arg71Pro (c.212G>C)?

PAH p.Arg71Pro (c.212G>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Arg71Pro (c.212G>C) in the general population?

PAH p.Arg71Pro (c.212G>C) is absent from gnomAD v4.1 (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.Arg71Pro (c.212G>C)?

AlphaMissense predicts ambiguous (score 0.3977) — an in-silico prediction, not a clinical call.

PAH p.Arg71Pro

c.212G>C · rs62508695 · VCV1480944

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3977 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

phenylketonuria

Computational evidence

Protein change
AlphaMissense	0.3977	ambiguous
REVEL	0.743	pathogenic-leaning
SaProt	LLR -9.65	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.4	GERP 1.4, phastCons 0.027
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAH
Protein: p.Arg71Pro
Coding: c.212G>C
MANE Select: NM_000277
dbSNP: rs62508695
Type: single nucleotide variant
Location: chr12:102894875 (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 71: the act domain; 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.Arg71His Likely pathogenic ★★★ ⚠ same residue
PAH p.Arg71Cys Uncertain significance ★★★ ⚠ same residue
PAH p.Arg71fs 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
PAH c.1066-11G>A Pathogenic ★★★ same condition
PAH c.1066-14C>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-arg71pro (accessed [today's date]).

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