Is ACSS2 p.Val496Ala (c.1487T>C) pathogenic?

ACSS2 p.Val496Ala (c.1487T>C) is classified Uncertain significance in ACSS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-11-20). AlphaMissense: ambiguous (0.4498); Low-frequency (popmax 1.39%, amr).

How common is ACSS2 p.Val496Ala (c.1487T>C) in the general population?

ACSS2 p.Val496Ala (c.1487T>C) is low-frequency (popmax 1.39%, amr) (gnomAD).

What do computational predictors say about ACSS2 p.Val496Ala (c.1487T>C)?

AlphaMissense predicts ambiguous (score 0.4498) — an in-silico prediction, not a clinical call.

ACSS2 p.Val496Ala

c.1487T>C · rs59088485 · VCV617833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4498 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.39%, amr)

Computational evidence

Protein change
AlphaMissense	0.4498	ambiguous
REVEL	0.566	indeterminate
SaProt	LLR -9.50	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 4e-07 · regional, not allelic
Overall
CADD	31.0	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 1.39% Admixed American · 832/59,988 alleles

Filtering AF 1.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.28%

Overall 0.0612% 987/1,614,062 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.39%	72
Remaining individualsnot grpmax-eligible	0.0784%	1,275
South Asian	0.0154%	6,505
European (non-Finnish)	0.00737%	13,563
African / African-American	0.00666%	15,009

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.Val496Ala
Coding: c.1487T>C
MANE Select: NM_018677
dbSNP: rs59088485
Type: single nucleotide variant
Location: chr20:34921805 (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-val496ala (accessed [today's date]).

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