Is ACSM5 p.Ile403Thr (c.1208T>C) pathogenic?

ACSM5 p.Ile403Thr (c.1208T>C) is classified Uncertain significance in ACSM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: ambiguous (0.4059); Ultra-rare (popmax 0.0267%, eas).

How common is ACSM5 p.Ile403Thr (c.1208T>C) in the general population?

ACSM5 p.Ile403Thr (c.1208T>C) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about ACSM5 p.Ile403Thr (c.1208T>C)?

AlphaMissense predicts ambiguous (score 0.4059) — an in-silico prediction, not a clinical call.

ACSM5 p.Ile403Thr

c.1208T>C · VCV4001093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4059 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Computational evidence

Protein change
AlphaMissense	0.4059	ambiguous
REVEL	0.499	indeterminate
SaProt	LLR -11.65	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 29 kb · p 0.91 · regional, not allelic
Overall
CADD	24.6	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 0.0267% East Asian · 12/44,886 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.00192% 31/1,613,750 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,740
African / African-American	0.00935%	10,701
South Asian	0.0011%	91,070
European (non-Finnish)	0.000932%	107,253

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.Ile403Thr
Coding: c.1208T>C
MANE Select: NM_017888
Type: single nucleotide variant
Location: chr16:20431221 (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-ile403thr (accessed [today's date]).

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