Is ACSM5 p.Val540Glu (c.1619T>A) pathogenic?

ACSM5 p.Val540Glu (c.1619T>A) is classified Uncertain significance in ACSM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely pathogenic (0.9536); Very rare (popmax 0.00534%, afr).

How common is ACSM5 p.Val540Glu (c.1619T>A) in the general population?

ACSM5 p.Val540Glu (c.1619T>A) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ACSM5 p.Val540Glu (c.1619T>A)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

ACSM5 p.Val540Glu

c.1619T>A · rs777898691 · VCV3140711

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic · top 4% in ACSM5
REVEL	0.666	pathogenic-leaning
SaProt	LLR -16.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 29 kb · p 0.91 · regional, not allelic
Overall
CADD	27.0	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 0.00534% African / African-American · 4/74,862 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,612,224 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: ACSM5
Protein: p.Val540Glu
Coding: c.1619T>A
MANE Select: NM_017888
dbSNP: rs777898691
Type: single nucleotide variant
Location: chr16:20439882 (GRCh38)
Gene constraint: LOEUF 1.003 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.58

Full ACSM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSM5 p.Pro144Leu Uncertain significance ★★ ⚠ same type
ACSM5 c.1001+10G>A Benign ★★ same type
ACSM5 p.His360Arg Benign ★★ same type
ACSM5 p.Ala160Val Uncertain significance ★ ⚠ same type
ACSM5 p.Ala163Ser Uncertain significance ★ ⚠ same type
ACSM5 p.Arg100Ser Uncertain significance ★ ⚠ same type
ACSM5 p.Arg157Trp Uncertain significance ★ ⚠ same type
ACSM5 p.Arg197Trp 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/acsm5-p-val540glu (accessed [today's date]).

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