Is ACSS3 p.Ile327Thr (c.980T>C) pathogenic?

ACSS3 p.Ile327Thr (c.980T>C) is classified Uncertain significance in ACSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.6405); Very rare (popmax 0.00267%, afr).

How common is ACSS3 p.Ile327Thr (c.980T>C) in the general population?

ACSS3 p.Ile327Thr (c.980T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ACSS3 p.Ile327Thr (c.980T>C)?

AlphaMissense predicts likely pathogenic (score 0.6405) — an in-silico prediction, not a clinical call.

ACSS3 p.Ile327Thr

c.980T>C · VCV3263474

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6405 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6405	likely pathogenic
REVEL	0.379	indeterminate
SaProt	LLR -10.93	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 177 kb · p 0.074 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,926 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.00149% 24/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,690
Remaining individualsnot grpmax-eligible	0.0032%	31,239
African / African-Americangrpmax	0.00267%	37,463
European (non-Finnish)	0.000763%	131,099

Ashkenazi Jewish 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: ACSS3
Protein: p.Ile327Thr
Coding: c.980T>C
MANE Select: NM_024560
Type: single nucleotide variant
Location: chr12:81151902 (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-ile327thr (accessed [today's date]).

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