Is ACACA p.Pro1318Ala (c.3952C>G) pathogenic?

ACACA p.Pro1318Ala (c.3952C>G) is classified Uncertain significance in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-20). AlphaMissense: likely benign (0.0541); Very rare (popmax 0.01%, amr).

How common is ACACA p.Pro1318Ala (c.3952C>G) in the general population?

ACACA p.Pro1318Ala (c.3952C>G) is very rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about ACACA p.Pro1318Ala (c.3952C>G)?

AlphaMissense predicts likely benign (score 0.0541) — an in-silico prediction, not a clinical call.

ACACA p.Pro1318Ala

c.3952C>G · rs768387542 · VCV2520265

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0541 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.01%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0541	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -6.25	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 9.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 18 kb · p 6e-10 · regional, not allelic
Overall
CADD	19.67	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1281A vs ClinVar P1318A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,012 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000434% 7/1,611,246 alleles · very rare exomes 7/1,459,010 · genomes 0/152,236 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,002
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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: ACACA
Protein: p.Pro1318Ala
Coding: c.3952C>G
MANE Select: NM_198834
dbSNP: rs768387542
Type: single nucleotide variant
Location: chr17:37205869 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB

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

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ACACA p.Arg745Trp Uncertain significance ★★ ⚠ same type
ACACA p.Asn1903Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
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ACACA p.Asp2228Asn 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/acaca-p-pro1318ala (accessed [today's date]).

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