Is ACMSD p.Leu39Phe (c.117G>T) pathogenic?

ACMSD p.Leu39Phe (c.117G>T) is classified Uncertain significance in ACMSD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-05). AlphaMissense: likely pathogenic (0.5792); Ultra-rare (popmax 0.0245%, eas).

How common is ACMSD p.Leu39Phe (c.117G>T) in the general population?

ACMSD p.Leu39Phe (c.117G>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about ACMSD p.Leu39Phe (c.117G>T)?

AlphaMissense predicts likely pathogenic (score 0.5792) — an in-silico prediction, not a clinical call.

ACMSD p.Leu39Phe

c.117G>T · rs539329795 · VCV3136971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5792	likely pathogenic
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.38	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 63 kb · p 0.52 · regional, not allelic
Overall
CADD	24.2	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 0.0245% East Asian · 11/44,876 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000805% 13/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,080
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,506

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: ACMSD
Protein: p.Leu39Phe
Coding: c.117G>T
MANE Select: NM_138326
dbSNP: rs539329795
Type: single nucleotide variant
Location: chr2:134859275 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.67 · 6 PDB
Residue 39: a β-strand

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

Similar variants

ACMSD p.Pro11= Benign ★★ same type
ACMSD c.677-14G>T Uncertain significance ★ same type
ACMSD c.948+1G>A Uncertain significance ★ same type
ACMSD p.Ala101Thr Uncertain significance ★ ⚠ same type
ACMSD p.Ala121Val Uncertain significance ★ ⚠ same type
ACMSD p.Ala154Val Uncertain significance ★ ⚠ same type
ACMSD p.Ala162Val Uncertain significance ★ ⚠ same type
ACMSD p.Ala223Thr 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/acmsd-p-leu39phe (accessed [today's date]).

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