Is ACSS3 p.Leu34Phe (c.100C>T) pathogenic?

ACSS3 p.Leu34Phe (c.100C>T) is classified Uncertain significance in ACSS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: likely benign (0.0925); Very rare (popmax 0.00112%, sas).

How common is ACSS3 p.Leu34Phe (c.100C>T) in the general population?

ACSS3 p.Leu34Phe (c.100C>T) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about ACSS3 p.Leu34Phe (c.100C>T)?

AlphaMissense predicts likely benign (score 0.0925) — an in-silico prediction, not a clinical call.

ACSS3 p.Leu34Phe

c.100C>T · rs1287024355 · VCV3141042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0925	likely benign
REVEL	0.027	moderately benign-leaning
SaProt	LLR -8.84	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 4.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 177 kb · p 0.074 · regional, not allelic
Overall
CADD	21.9	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 0.00112% South Asian · 1/89,400 alleles

Overall 6.94e-05% 1/1,440,072 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: ACSS3
Protein: p.Leu34Phe
Coding: c.100C>T
MANE Select: NM_024560
dbSNP: rs1287024355
Type: single nucleotide variant
Location: chr12:81078220 (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-leu34phe (accessed [today's date]).

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