Is ACAA2 p.Lys312Thr (c.935A>C) pathogenic?

ACAA2 p.Lys312Thr (c.935A>C) is classified Uncertain significance in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-25). AlphaMissense: likely benign (0.1222); Ultra-rare (popmax 0.0325%, afr).

How common is ACAA2 p.Lys312Thr (c.935A>C) in the general population?

ACAA2 p.Lys312Thr (c.935A>C) is ultra-rare (popmax 0.0325%, afr) (gnomAD).

What do computational predictors say about ACAA2 p.Lys312Thr (c.935A>C)?

AlphaMissense predicts likely benign (score 0.1222) — an in-silico prediction, not a clinical call.

ACAA2 p.Lys312Thr

c.935A>C · VCV3455278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1222 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1222	likely benign
REVEL	0.365	indeterminate
SaProt	LLR -10.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	19.74	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0325% African / African-American · 22/67,642 alleles

Filtering AF 0.0219% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0185%

Overall 0.00157% 23/1,467,098 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0325%	3,075
Remaining individualsnot grpmax-eligible	0.00178%	56,300

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: ACAA2
Protein: p.Lys312Thr
Coding: c.935A>C
MANE Select: NM_006111
Type: single nucleotide variant
Location: chr18:49787310 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.49 · 2 PDB
Residue 312: a modified residue (n6-acetyllysine; alternate); a modified residue (n6-succinyllysine; alternate); an α-helix

Full ACAA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAA2 p.Lys312Asn Uncertain significance ★ ⚠ same residue
ACAA2 p.Tyr198Asn Benign ★★ same type
ACAA2 p.Ala183Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala196Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala250Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala267Gly Uncertain significance ★ ⚠ same type
ACAA2 p.Ala70Ser Uncertain significance ★ ⚠ same type
ACAA2 p.Arg133His 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/acaa2-p-lys312thr (accessed [today's date]).

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