Is ACSS2 p.Arg153Gln (c.458G>A) pathogenic?

ACSS2 p.Arg153Gln (c.458G>A) is classified Uncertain significance in ACSS2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-23). AlphaMissense: likely benign (0.0875); Ultra-rare (popmax 0.0164%, mid); Associated with ACSS2-related disorder.

What condition is associated with ACSS2 p.Arg153Gln (c.458G>A)?

ACSS2 p.Arg153Gln (c.458G>A) is associated with ACSS2-related disorder (ClinVar).

How common is ACSS2 p.Arg153Gln (c.458G>A) in the general population?

ACSS2 p.Arg153Gln (c.458G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ACSS2 p.Arg153Gln (c.458G>A)?

AlphaMissense predicts likely benign (score 0.0875) — an in-silico prediction, not a clinical call.

ACSS2 p.Arg153Gln

c.458G>A · VCV3355389

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0875 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACSS2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0875	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.58	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 2.5	GERP 0.42, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 51 kb · p 4e-07 · regional, not allelic
Overall
CADD	20.8	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00724% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00676%

Overall 0.00669% 108/1,613,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00864%	11,569
Remaining individualsnot grpmax-eligible	0.0048%	20,827
East Asian	0.00223%	44,882
African / African-American	0.00134%	74,888

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.Arg153Gln
Coding: c.458G>A
MANE Select: NM_018677
Type: single nucleotide variant
Location: chr20:34913179 (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.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
ACSS2 p.Thr628= 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-arg153gln (accessed [today's date]).

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