Is GPAA1 p.Ala74Val (c.221C>T) pathogenic?

GPAA1 p.Ala74Val (c.221C>T) is classified Uncertain significance in GPAA1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-29). AlphaMissense: ambiguous (0.3598); Very rare (popmax 0.00441%, sas).

How common is GPAA1 p.Ala74Val (c.221C>T) in the general population?

GPAA1 p.Ala74Val (c.221C>T) is very rare (popmax 0.00441%, sas) (gnomAD).

What do computational predictors say about GPAA1 p.Ala74Val (c.221C>T)?

AlphaMissense predicts ambiguous (score 0.3598) — an in-silico prediction, not a clinical call.

GPAA1 p.Ala74Val

c.221C>T · rs782793294 · VCV1505422

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3598 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3598	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -8.90	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 0.65, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	21.2	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

Grpmax group 0.00441% South Asian · 4/90,644 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000686% 11/1,603,444 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00441%	22,661
African / African-American	0.00134%	74,676
European (non-Finnish)	0.000511%	195,566

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: GPAA1
Protein: p.Ala74Val
Coding: c.221C>T
MANE Select: NM_003801
dbSNP: rs782793294
Type: single nucleotide variant
Location: chr8:144083270 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 74: an α-helix

Full GPAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPAA1 p.Ala74Ser Uncertain significance ★★ ⚠ same residue
GPAA1 c.1165-1C>T Likely pathogenic ★★ same type
GPAA1 c.366+1G>A Likely pathogenic ★★ same type
GPAA1 c.616+1G>T Likely pathogenic ★★ same type
GPAA1 p.Arg215Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 p.Leu291Pro Likely pathogenic ★★ same type
GPAA1 p.Ser419Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 c.1164+1A>G Uncertain significance ★★ same type

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/gpaa1-p-ala74val (accessed [today's date]).

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