Is AP5S1 p.Val125Met (c.373G>A) pathogenic?

AP5S1 p.Val125Met (c.373G>A) is classified Uncertain significance in AP5S1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-30). AlphaMissense: likely pathogenic (0.5773); Very rare (popmax 0.00144%, nfe).

How common is AP5S1 p.Val125Met (c.373G>A) in the general population?

AP5S1 p.Val125Met (c.373G>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about AP5S1 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.5773) — an in-silico prediction, not a clinical call.

AP5S1 p.Val125Met

c.373G>A · rs777555624 · VCV2223571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5773 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5773	likely pathogenic
REVEL	0.279	benign-leaning
SaProt	LLR -9.60	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 0.88, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 2,176 bp · p 0.23 · regional, not allelic
Overall
CADD	25.9	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 0.00144% European (non-Finnish) · 17/1,180,034 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00105% 17/1,613,834 alleles · very rare exomes 16/1,461,602 · genomes 1/152,232 · joint denominator

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: AP5S1
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_018347
dbSNP: rs777555624
Type: single nucleotide variant
Location: chr20:3824067 (GRCh38)
Gene constraint: LOEUF 1.528 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.72 · 2 PDB
Residue 125: a β-strand

Full AP5S1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP5S1 p.Arg74Gln Uncertain significance ★★ ⚠ same type
AP5S1 p.Ala101Glu Uncertain significance ★ ⚠ same type
AP5S1 p.Ala102Thr Uncertain significance ★ ⚠ same type
AP5S1 p.Ala102Val Uncertain significance ★ ⚠ same type
AP5S1 p.Ala128Gly Uncertain significance ★ ⚠ same type
AP5S1 p.Ala154Val Uncertain significance ★ ⚠ same type
AP5S1 p.Arg110Trp Uncertain significance ★ ⚠ same type
AP5S1 p.Arg140Trp 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/ap5s1-p-val125met (accessed [today's date]).

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