Is AP1M1 p.Val77Met (c.229G>A) pathogenic?

AP1M1 p.Val77Met (c.229G>A) is classified Uncertain significance in AP1M1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.6069); Very rare (popmax 0.00329%, sas).

How common is AP1M1 p.Val77Met (c.229G>A) in the general population?

AP1M1 p.Val77Met (c.229G>A) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about AP1M1 p.Val77Met (c.229G>A)?

AlphaMissense predicts likely pathogenic (score 0.6069) — an in-silico prediction, not a clinical call.

AP1M1 p.Val77Met

c.229G>A · VCV3300368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6069 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6069	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 35 kb · p 1.4e-14 · regional, not allelic
Overall
CADD	26.5	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 0.00329% South Asian · 3/91,082 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000867% 14/1,614,030 alleles · very rare exomes 12/1,461,850 · genomes 2/152,180 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,361
African / African-American	0.00267%	37,463
East Asian	0.00223%	44,884
European (non-Finnish)	0.000678%	147,504

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: AP1M1
Protein: p.Val77Met
Coding: c.229G>A
MANE Select: NM_032493
Type: single nucleotide variant
Location: chr19:16206370 (GRCh38)
Gene constraint: LOEUF 0.474 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.41

Full AP1M1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AP1M1 p.Ala75Val Uncertain significance ★ ⚠ same type
AP1M1 p.Arg104Trp Uncertain significance ★ ⚠ same type
AP1M1 p.Arg148Gln Uncertain significance ★ ⚠ same type
AP1M1 p.Arg191Cys Uncertain significance ★ ⚠ same type
AP1M1 p.Arg22Cys Uncertain significance ★ ⚠ same type
AP1M1 p.Arg22His Uncertain significance ★ ⚠ same type
AP1M1 p.Arg246His Uncertain significance ★ ⚠ same type
AP1M1 p.Arg410His 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/ap1m1-p-val77met (accessed [today's date]).

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