Is ACSM2B p.Arg461Trp (c.1381C>T) pathogenic?

ACSM2B p.Arg461Trp (c.1381C>T) is classified Uncertain significance in ACSM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.596); Ultra-rare (popmax 0.0367%, amr).

How common is ACSM2B p.Arg461Trp (c.1381C>T) in the general population?

ACSM2B p.Arg461Trp (c.1381C>T) is ultra-rare (popmax 0.0367%, amr) (gnomAD).

What do computational predictors say about ACSM2B p.Arg461Trp (c.1381C>T)?

AlphaMissense predicts likely pathogenic (score 0.596) — an in-silico prediction, not a clinical call.

ACSM2B p.Arg461Trp

c.1381C>T · rs143500332 · VCV2348160

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.596 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0367%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.596	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -15.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.1	GERP -3.4
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.38 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0367% Admixed American · 22/60,010 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0209%

Overall 0.0127% 205/1,613,784 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0367%	2,728
African / African-American	0.0227%	4,405
Middle Eastern	0.0165%	6,056
European (non-Finnish)	0.0129%	7,762
Remaining individualsnot grpmax-eligible	0.0096%	10,414
East Asian	0.00891%	11,220
South Asian	0.00329%	30,359

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: ACSM2B
Protein: p.Arg461Trp
Coding: c.1381C>T
MANE Select: NM_001105069
dbSNP: rs143500332
Type: single nucleotide variant
Location: chr16:20543163 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.41
Residue 461: a binding site

Full ACSM2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSM2B p.Arg461Gln Uncertain significance ★ ⚠ same residue
ACSM2B p.Ile305Val Benign ★★ same type
ACSM2B p.Pro312= Benign ★★ same type
ACSM2B p.Ser272= Benign ★★ same type
ACSM2B p.Ala231Ser Uncertain significance ★ ⚠ same type
ACSM2B p.Ala387Val Uncertain significance ★ ⚠ same type
ACSM2B p.Ala487Asp Uncertain significance ★ ⚠ same type
ACSM2B p.Arg148Lys 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/acsm2b-p-arg461trp (accessed [today's date]).

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