Is ACMSD p.Lys275Arg (c.824A>G) pathogenic?

ACMSD p.Lys275Arg (c.824A>G) is classified Uncertain significance in ACMSD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: likely benign (0.0737); Ultra-rare (popmax 0.0165%, mid).

How common is ACMSD p.Lys275Arg (c.824A>G) in the general population?

ACMSD p.Lys275Arg (c.824A>G) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACMSD p.Lys275Arg (c.824A>G)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

ACMSD p.Lys275Arg

c.824A>G · rs151324307 · VCV2255532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 63 kb · p 0.52 · regional, not allelic
Overall
CADD	19.19	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00223% 36/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,974
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0048%	20,835
Admixed American	0.00167%	60,014
European (non-Finnish)	0.00136%	73,750

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Lys275Arg
Coding: c.824A>G
MANE Select: NM_138326
dbSNP: rs151324307
Type: single nucleotide variant
Location: chr2:134872616 (GRCh38)
Gene constraint: LOEUF 1.063 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.67 · 6 PDB
Residue 275: an α-helix

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-lys275arg (accessed [today's date]).

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