Is ACSS2 p.Glu445Gln (c.1333G>C) pathogenic?

ACSS2 p.Glu445Gln (c.1333G>C) is classified Uncertain significance in ACSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely benign (0.2259); Very rare (popmax 0.00267%, afr).

How common is ACSS2 p.Glu445Gln (c.1333G>C) in the general population?

ACSS2 p.Glu445Gln (c.1333G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ACSS2 p.Glu445Gln (c.1333G>C)?

AlphaMissense predicts likely benign (score 0.2259) — an in-silico prediction, not a clinical call.

ACSS2 p.Glu445Gln

c.1333G>C · VCV4637074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2259 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2259	likely benign
REVEL	0.462	indeterminate
SaProt	LLR -11.32	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.4, 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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,938 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00131% 2/152,190 alleles · very rare

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.Glu445Gln
Coding: c.1333G>C
MANE Select: NM_018677
Type: single nucleotide variant
Location: chr20:34921385 (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-glu445gln (accessed [today's date]).

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