Is ACSS3 p.Asp488Gly (c.1463A>G) pathogenic?

ACSS3 p.Asp488Gly (c.1463A>G) is classified Uncertain significance in ACSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: likely benign (0.2104); Very rare (popmax 0.00195%, amr).

How common is ACSS3 p.Asp488Gly (c.1463A>G) in the general population?

ACSS3 p.Asp488Gly (c.1463A>G) is very rare (popmax 0.00195%, amr) (gnomAD).

What do computational predictors say about ACSS3 p.Asp488Gly (c.1463A>G)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

ACSS3 p.Asp488Gly

c.1463A>G · VCV4637087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.625	indeterminate
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.49	acceptor loss, 12 bp away · masked 0 · deltas
Pangolin	Δ0.45	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 177 kb · p 0.074 · regional, not allelic
Overall
CADD	29.4	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 0.00195% Admixed American · 1/51,238 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000216% 3/1,386,678 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00195%	51,238
European (non-Finnish)	0.000175%	571,331

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: ACSS3
Protein: p.Asp488Gly
Coding: c.1463A>G
MANE Select: NM_024560
Type: single nucleotide variant
Location: chr12:81220025 (GRCh38)
Gene constraint: LOEUF 0.931 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.93

Full ACSS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSS3 p.Ala193Thr Uncertain significance ★ ⚠ same type
ACSS3 p.Ala262Glu Uncertain significance ★ ⚠ same type
ACSS3 p.Ala317Thr Uncertain significance ★ ⚠ same type
ACSS3 p.Ala377Thr Uncertain significance ★ ⚠ same type
ACSS3 p.Ala53Glu Uncertain significance ★ ⚠ same type
ACSS3 p.Ala570Thr Uncertain significance ★ ⚠ same type
ACSS3 p.Ala657Asp Uncertain significance ★ ⚠ same type
ACSS3 p.Ala80Val 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/acss3-p-asp488gly (accessed [today's date]).

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