Is AMER3 p.Val238Met (c.712G>A) pathogenic?

AMER3 p.Val238Met (c.712G>A) is classified Uncertain significance in AMER3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-27). AlphaMissense: likely benign (0.3343); Very rare (popmax 0.00447%, eas).

How common is AMER3 p.Val238Met (c.712G>A) in the general population?

AMER3 p.Val238Met (c.712G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about AMER3 p.Val238Met (c.712G>A)?

AlphaMissense predicts likely benign (score 0.3343) — an in-silico prediction, not a clinical call.

AMER3 p.Val238Met

c.712G>A · VCV3292570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3343 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3343	likely benign
REVEL	0.371	indeterminate
SaProt	LLR -6.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.69, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,582 bp · p 0.068 · regional, not allelic
Overall
CADD	24.1	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 0.00447% East Asian · 2/44,758 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00161% 26/1,611,166 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,379
African / African-American	0.00401%	24,957
Admixed American	0.00334%	29,977
Remaining individualsnot grpmax-eligible	0.0016%	62,324
European (non-Finnish)	0.00144%	69,316
South Asian	0.0011%	90,964

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: AMER3
Protein: p.Val238Met
Coding: c.712G>A
MANE Select: NM_152698
Type: single nucleotide variant
Location: chr2:130762784 (GRCh38)
Structure: AlphaFold pLDDT 45.30

Full AMER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMER3 p.Val238Ala Uncertain significance ★ ⚠ same residue
AMER3 p.Ala175Val Uncertain significance ★ ⚠ same type
AMER3 p.Ala25Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala345Ser Uncertain significance ★ ⚠ same type
AMER3 p.Ala402Asp Uncertain significance ★ ⚠ same type
AMER3 p.Ala557Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala55Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala579Thr 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/amer3-p-val238met (accessed [today's date]).

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