Is ACACA p.Pro2214His (c.6641C>A) pathogenic?

ACACA p.Pro2214His (c.6641C>A) is classified Pathogenic/Likely pathogenic in ACACA (ClinVar, No assertion criteria, 2 submitters; last evaluated 2024-01-31). AlphaMissense: likely pathogenic (0.6274); Absent from gnomAD v4.1; Associated with acetyl-coa carboxylase deficiency.

What condition is associated with ACACA p.Pro2214His (c.6641C>A)?

ACACA p.Pro2214His (c.6641C>A) is associated with acetyl-coa carboxylase deficiency (ClinVar).

How common is ACACA p.Pro2214His (c.6641C>A) in the general population?

ACACA p.Pro2214His (c.6641C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACACA p.Pro2214His (c.6641C>A)?

AlphaMissense predicts likely pathogenic (score 0.6274) — an in-silico prediction, not a clinical call.

ACACA p.Pro2214His

c.6641C>A · rs2544608353 · VCV1799553

Pathogenic/Likely pathogenic No assertion criteria

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6274 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

acetyl-coa carboxylase deficiency

Computational evidence

Protein change
AlphaMissense	0.6274	likely pathogenic ✓ concordant with ClinVar
REVEL	0.555	indeterminate
SaProt	LLR -12.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 101 kb · p 4.3e-52 · regional, not allelic
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2177H vs ClinVar P2214H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACACA
Protein: p.Pro2214His
Coding: c.6641C>A
MANE Select: NM_198834
dbSNP: rs2544608353
Type: single nucleotide variant
Location: chr17:37097909 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 2177 UniProt numbering: an α-helix; the coa carboxyltransferase c-terminal domain; the 'carboxyltransferase' region

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

Disease context

acetyl-coa carboxylase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same condition
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same condition
ACACA p.Gln641= Benign ★★ same condition
ACACA p.Ala1548Thr Uncertain significance ★ ⚠ same condition
ACACA p.Arg2198Trp Uncertain significance ★ ⚠ same condition
ACACA p.Ala1657Thr Pathogenic ⚠ same condition
ACACA c.3474+2TA[14] Uncertain significance ★ same condition
ACACA p.Arg1206His 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-pro2214his (accessed [today's date]).

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