Is ACAA2 p.Arg5Leu (c.14G>T) pathogenic?

ACAA2 p.Arg5Leu (c.14G>T) is classified Uncertain significance in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-04). AlphaMissense: ambiguous (0.4832); Rare (popmax 0.163%, afr).

How common is ACAA2 p.Arg5Leu (c.14G>T) in the general population?

ACAA2 p.Arg5Leu (c.14G>T) is rare (popmax 0.163%, afr) (gnomAD).

What do computational predictors say about ACAA2 p.Arg5Leu (c.14G>T)?

AlphaMissense predicts ambiguous (score 0.4832) — an in-silico prediction, not a clinical call.

ACAA2 p.Arg5Leu

c.14G>T · VCV3995406

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4832 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.163%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4832	ambiguous
REVEL	0.667	pathogenic-leaning
SaProt	LLR -12.59	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 2.7, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	31.0	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 0.163% African / African-American · 105/64,438 alleles

Filtering AF 0.138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.00877% 109/1,242,308 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.163%	614
Remaining individualsnot grpmax-eligible	0.00654%	15,295
Admixed American	0.00422%	23,714

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.Arg5Leu
Coding: c.14G>T
MANE Select: NM_006111
Type: single nucleotide variant
Location: chr18:49813471 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.49 · 2 PDB

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

Similar variants

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
ACAA2 p.Arg371Cys 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-arg5leu (accessed [today's date]).

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