Is ACSM2B p.Pro475His (c.1424C>A) pathogenic?

ACSM2B p.Pro475His (c.1424C>A) is classified Uncertain significance in ACSM2B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.6292); Ultra-rare (popmax 0.0494%, mid).

How common is ACSM2B p.Pro475His (c.1424C>A) in the general population?

ACSM2B p.Pro475His (c.1424C>A) is ultra-rare (popmax 0.0494%, mid) (gnomAD).

What do computational predictors say about ACSM2B p.Pro475His (c.1424C>A)?

AlphaMissense predicts likely pathogenic (score 0.6292) — an in-silico prediction, not a clinical call.

ACSM2B p.Pro475His

c.1424C>A · VCV4219758

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6292	likely pathogenic
REVEL	0.53	indeterminate
SaProt	LLR -15.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.38 · regional, not allelic
Overall
CADD	25.6	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 0.0494% Middle Eastern · 3/6,078 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00716%

Overall 0.00403% 65/1,613,408 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0494%	2,026
European (non-Finnish)	0.00509%	19,664
East Asian	0.00223%	44,888
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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.Pro475His
Coding: c.1424C>A
MANE Select: NM_001105069
Type: single nucleotide variant
Location: chr16:20542999 (GRCh38)
Gene constraint: LOEUF 0.956 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.41

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

Similar variants

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
ACSM2B p.Arg447Gln 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-pro475his (accessed [today's date]).

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