Is APH1A p.Val253Met (c.757G>A) pathogenic?

APH1A p.Val253Met (c.757G>A) is classified Uncertain significance in APH1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.2351); Ultra-rare (popmax 0.0112%, eas).

How common is APH1A p.Val253Met (c.757G>A) in the general population?

APH1A p.Val253Met (c.757G>A) is ultra-rare (popmax 0.0112%, eas) (gnomAD).

What do computational predictors say about APH1A p.Val253Met (c.757G>A)?

AlphaMissense predicts likely benign (score 0.2351) — an in-silico prediction, not a clinical call.

APH1A p.Val253Met

c.757G>A · VCV4123191

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0112%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2351	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.30	acceptor gain, 23 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 2,677 bp · p 4.4e-07 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0112% East Asian · 5/44,452 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00278%

Overall 0.00328% 5/152,318 alleles · ultra-rare

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: APH1A
Protein: p.Val253Met
Coding: c.757G>A
MANE Select: NM_001077628
Type: single nucleotide variant
Location: chr1:150266171 (GRCh38)
Gene constraint: LOEUF 0.806 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.69 · 25 PDB

Full APH1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APH1A p.Ala37Ser Uncertain significance ★ ⚠ same type
APH1A p.Ala49Ser Uncertain significance ★ ⚠ same type
APH1A p.Arg109Gly Uncertain significance ★ ⚠ same type
APH1A p.Arg186Trp Uncertain significance ★ ⚠ same type
APH1A p.Arg241Gly Uncertain significance ★ ⚠ same type
APH1A p.Arg241His Uncertain significance ★ ⚠ same type
APH1A p.Arg66Trp Uncertain significance ★ ⚠ same type
APH1A p.Asp61Asn 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/aph1a-p-val253met (accessed [today's date]).

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