Is ACSS2 p.Val330Ala (c.989T>C) pathogenic?

ACSS2 p.Val330Ala (c.989T>C) is classified Benign in ACSS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-12-16). AlphaMissense: likely benign (0.187); Rare (popmax 0.344%, nfe); Associated with ACSS2-related disorder.

What condition is associated with ACSS2 p.Val330Ala (c.989T>C)?

ACSS2 p.Val330Ala (c.989T>C) is associated with ACSS2-related disorder (ClinVar).

How common is ACSS2 p.Val330Ala (c.989T>C) in the general population?

ACSS2 p.Val330Ala (c.989T>C) is rare (popmax 0.344%, nfe) (gnomAD).

What do computational predictors say about ACSS2 p.Val330Ala (c.989T>C)?

AlphaMissense predicts likely benign (score 0.187) — an in-silico prediction, not a clinical call.

ACSS2 p.Val330Ala

c.989T>C · rs59126805 · VCV3045466

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.187 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.344%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACSS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.187	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -1.93	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 2.7	GERP 0.042, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 4e-07 · regional, not allelic
Overall
CADD	21.7	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 0.344% European (non-Finnish) · 4,064/1,179,950 alleles

Filtering AF 0.336% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.332%

Overall 0.299% 4,828/1,613,956 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.768%	130
European (non-Finnish)grpmax	0.344%	290
Remaining individualsnot grpmax-eligible	0.232%	431
Admixed American	0.12%	834
African / African-American	0.0586%	1,706
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,919
South Asian	0.00769%	13,006

Finnish 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: ACSS2
Protein: p.Val330Ala
Coding: c.989T>C
MANE Select: NM_018677
dbSNP: rs59126805
Type: single nucleotide variant
Location: chr20:34920555 (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

Disease context

ACSS2-related disorder

Similar variants

ACSS2 p.Arg153Gln Uncertain significance ⚠ same condition
ACSS2 p.Arg696His Uncertain significance same condition
ACSS2 p.Ala307= Likely benign same condition
ACSS2 p.Asp309= Likely benign same condition
ACSS2 p.His252= Benign same condition
ACSS2 p.Lys342= Likely benign same condition
ACSS2 p.Pro486= Likely benign same condition
ACSS2 p.Thr137= Likely benign same condition

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-val330ala (accessed [today's date]).

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