Is ACSS1 p.Pro28Leu (c.83C>T) pathogenic?

ACSS1 p.Pro28Leu (c.83C>T) is classified Uncertain significance in ACSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-29). AlphaMissense: likely benign (0.0794); Very rare (popmax 9.24e-05%, nfe).

How common is ACSS1 p.Pro28Leu (c.83C>T) in the general population?

ACSS1 p.Pro28Leu (c.83C>T) is very rare (popmax 9.24e-05%, nfe) (gnomAD).

What do computational predictors say about ACSS1 p.Pro28Leu (c.83C>T)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

ACSS1 p.Pro28Leu

c.83C>T · VCV4637061

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.24e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.38	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 -1.9	GERP -1.9
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.75 · regional, not allelic
Overall
CADD	1.83	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 9.24e-05% European (non-Finnish) · 1/1,081,846 alleles

Overall 8.04e-05% 1/1,244,002 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: ACSS1
Protein: p.Pro28Leu
Coding: c.83C>T
MANE Select: NM_032501
Type: single nucleotide variant
Location: chr20:25058020 (GRCh38)
Gene constraint: LOEUF 0.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.07 · 9 PDB
Residue 28: the 'disordered' region

Full ACSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACSS1 p.Val479Ile Benign ★★ ⚠ same type
ACSS1 p.Ala181Gly Uncertain significance ★ ⚠ same type
ACSS1 p.Ala211Val Uncertain significance ★ ⚠ same type
ACSS1 p.Ala279Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala316Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala37Glu Uncertain significance ★ ⚠ same type
ACSS1 p.Ala454Thr Uncertain significance ★ ⚠ same type
ACSS1 p.Ala602Val 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/acss1-p-pro28leu (accessed [today's date]).

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