Is PAH p.Leu321= (c.963C>T) pathogenic?

PAH p.Leu321= (c.963C>T) is classified Benign in PAH (ClinVar, Expert panel, 9 submitters; last evaluated 2018-07-29). Common (popmax 5.29%, afr) — too common for a highly-penetrant pathogenic allele; Associated with phenylketonuria.

What condition is associated with PAH p.Leu321= (c.963C>T)?

PAH p.Leu321= (c.963C>T) is associated with phenylketonuria (ClinVar).

How is Phenylketonuria inherited?

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

PAH p.Leu321=

Q: How common is PAH p.Leu321= (c.963C>T) in the general population?

PAH p.Leu321= (c.963C>T) is common (popmax 5.29%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.963C>T · rs61747292 · VCV102911

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 5.29%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Benign for phenylketonuria. Applied ACMG criteria (verbatim):

BS2 BS1 BP7 BS3_Supporting

Curation rationale (ClinGen, verbatim)

PAH-specific ACMG/AMP criteria applied: BS1: >0.02% as set by the PAH specific specifications; BP7: ; BS3_Supporting: cDNA method demonstrates 98% and intinic system demonstrates 81% residual enzyme activity; BS2: 38 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BP7, BS3_Supporting, BS2).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP -5.6	GERP -4.4
Overall
CADD	1.986	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.29% African / African-American · 3,962/74,930 alleles

Filtering AF 5.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.09%

Overall 0.277% 4,473/1,613,290 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.29%	19
Remaining individualsnot grpmax-eligible	0.407%	246
Admixed American	0.338%	296
Middle Eastern	0.264%	379
South Asian	0.0187%	5,356
European (non-Finnish)	0.00178%	56,161

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.Leu321=
Coding: c.963C>T
MANE Select: NM_000277
dbSNP: rs61747292
Type: single nucleotide variant
Location: chr12:102846901 (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 321: an α-helix

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.Leu321Ile Uncertain significance ★ ⚠ 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
PAH c.1066-1G>A Pathogenic ★★★ same condition
PAH c.1066-1G>C 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-leu321 (accessed [today's date]).

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