Is ACSS2 p.Asp231His (c.691G>C) pathogenic?

ACSS2 p.Asp231His (c.691G>C) is classified Uncertain significance in ACSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-11). AlphaMissense: likely pathogenic (0.6845); Ultra-rare (popmax 0.037%, nfe).

How common is ACSS2 p.Asp231His (c.691G>C) in the general population?

ACSS2 p.Asp231His (c.691G>C) is ultra-rare (popmax 0.037%, nfe) (gnomAD).

What do computational predictors say about ACSS2 p.Asp231His (c.691G>C)?

AlphaMissense predicts likely pathogenic (score 0.6845) — an in-silico prediction, not a clinical call.

ACSS2 p.Asp231His

c.691G>C · rs148166087 · VCV2366479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6845	likely pathogenic
REVEL	0.476	indeterminate
SaProt	LLR -11.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 4e-07 · regional, not allelic
Overall
CADD	29.4	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 0.037% European (non-Finnish) · 437/1,180,024 alleles

Filtering AF 0.0342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0279% 450/1,614,210 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.037%	2,700
Remaining individualsnot grpmax-eligible	0.0144%	6,945
African / African-American	0.00533%	18,765

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: ACSS2
Protein: p.Asp231His
Coding: c.691G>C
MANE Select: NM_018677
dbSNP: rs148166087
Type: single nucleotide variant
Location: chr20:34914143 (GRCh38)
Gene constraint: LOEUF 0.785 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.14

Full ACSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSS2 p.Cys300Ser Benign ★★ ⚠ same type
ACSS2 p.Pro42Thr Benign ★★ same type
ACSS2 c.834+791A>T Uncertain significance ★ same type
ACSS2 c.834+805C>T Uncertain significance ★ same type
ACSS2 c.834+806G>A Uncertain significance ★ same type
ACSS2 p.Ala181Val Uncertain significance ★ ⚠ same type
ACSS2 p.Ala233Asp Uncertain significance ★ ⚠ same type
ACSS2 p.Ala430Ser 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/acss2-p-asp231his (accessed [today's date]).

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