Is ACSM5 p.Arg100Ser (c.300G>C) pathogenic?

ACSM5 p.Arg100Ser (c.300G>C) is classified Uncertain significance in ACSM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.3621); Very rare (popmax 0.000254%, nfe).

How common is ACSM5 p.Arg100Ser (c.300G>C) in the general population?

ACSM5 p.Arg100Ser (c.300G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ACSM5 p.Arg100Ser (c.300G>C)?

AlphaMissense predicts ambiguous (score 0.3621) — an in-silico prediction, not a clinical call.

ACSM5 p.Arg100Ser

c.300G>C · VCV4220179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3621 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3621	ambiguous
REVEL	0.244	benign-leaning
SaProt	LLR -9.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.48	GERP 1.8, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 29 kb · p 0.91 · regional, not allelic
Overall
CADD	23.4	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 0.000254% European (non-Finnish) · 3/1,179,916 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,348 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.Arg100Ser
Coding: c.300G>C
MANE Select: NM_017888
Type: single nucleotide variant
Location: chr16:20418154 (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.Arg157Trp Uncertain significance ★ ⚠ same type
ACSM5 p.Arg197Trp Uncertain significance ★ ⚠ same type
ACSM5 p.Arg208Trp 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-arg100ser (accessed [today's date]).

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