Is AP5M1 p.Val69Ala (c.206T>C) pathogenic?

AP5M1 p.Val69Ala (c.206T>C) is classified Uncertain significance in AP5M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.1228); Very rare (popmax 8.47e-05%, nfe).

How common is AP5M1 p.Val69Ala (c.206T>C) in the general population?

AP5M1 p.Val69Ala (c.206T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about AP5M1 p.Val69Ala (c.206T>C)?

AlphaMissense predicts likely benign (score 0.1228) — an in-silico prediction, not a clinical call.

AP5M1 p.Val69Ala

c.206T>C · VCV3404658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1228 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1228	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.034, phastCons 0.97
Regional constraint	o/e 0.99	unconstrained · MANE · 14 kb · p 0.79 · regional, not allelic
Overall
CADD	16.57	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 8.47e-05% European (non-Finnish) · 1/1,180,022 alleles

Overall 6.84e-05% 1/1,461,870 alleles · very 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: AP5M1
Protein: p.Val69Ala
Coding: c.206T>C
MANE Select: NM_018229
Type: single nucleotide variant
Location: chr14:57274375 (GRCh38)
Gene constraint: LOEUF 1.061 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.31

Full AP5M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP5M1 p.Arg33Ter Likely pathogenic ★ same type
AP5M1 p.Trp389Ter Likely pathogenic ★ same type
AP5M1 p.Ala446Thr Uncertain significance ★ ⚠ same type
AP5M1 p.Ala54Val Uncertain significance ★ ⚠ same type
AP5M1 p.Ala5Thr Uncertain significance ★ ⚠ same type
AP5M1 p.Ala98Gly Uncertain significance ★ ⚠ same type
AP5M1 p.Arg119His Uncertain significance ★ ⚠ same type
AP5M1 p.Arg33Gln 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/ap5m1-p-val69ala (accessed [today's date]).

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