Is ACSS2 p.Ala181Val (c.542C>T) pathogenic?

ACSS2 p.Ala181Val (c.542C>T) is classified Uncertain significance in ACSS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-06-11). AlphaMissense: likely benign (0.2255); Rare (popmax 0.235%, nfe).

How common is ACSS2 p.Ala181Val (c.542C>T) in the general population?

ACSS2 p.Ala181Val (c.542C>T) is rare (popmax 0.235%, nfe) (gnomAD).

What do computational predictors say about ACSS2 p.Ala181Val (c.542C>T)?

AlphaMissense predicts likely benign (score 0.2255) — an in-silico prediction, not a clinical call.

ACSS2 p.Ala181Val

c.542C>T · rs112012777 · VCV3141008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2255 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.235%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2255	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -9.45	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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 4e-07 · regional, not allelic
Overall
CADD	22.3	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 0.235% European (non-Finnish) · 2,770/1,179,934 alleles

Filtering AF 0.227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.224%

Overall 0.178% 2,865/1,613,898 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.235%	426
Remaining individualsnot grpmax-eligible	0.088%	1,136
African / African-American	0.0453%	2,206
Finnishnot grpmax-eligible	0.00625%	15,994
Admixed American	0.00333%	29,997

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.Ala181Val
Coding: c.542C>T
MANE Select: NM_018677
dbSNP: rs112012777
Type: single nucleotide variant
Location: chr20:34913468 (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.Ala233Asp Uncertain significance ★ ⚠ same type
ACSS2 p.Ala430Ser Uncertain significance ★ ⚠ same type
ACSS2 p.Ala446Val 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-ala181val (accessed [today's date]).

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