Is ACACA p.Arg875Trp (c.2623C>T) pathogenic?

ACACA p.Arg875Trp (c.2623C>T) is classified Likely benign in ACACA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0778); Rare (popmax 0.57%, eas).

How common is ACACA p.Arg875Trp (c.2623C>T) in the general population?

ACACA p.Arg875Trp (c.2623C>T) is rare (popmax 0.57%, eas) (gnomAD).

What do computational predictors say about ACACA p.Arg875Trp (c.2623C>T)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

ACACA p.Arg875Trp

c.2623C>T · rs2287351 · VCV1990279

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.57%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -9.58	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 4.8	GERP 1.7, phastCons 0.96
Regional constraint	o/e 0.58	unconstrained · MANE · 26 kb · p 4.1e-22 · regional, not allelic
Overall
CADD	22.8	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 R838W vs ClinVar R875W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.57% East Asian · 256/44,880 alleles

Filtering AF 0.513% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.491%

Overall 0.0409% 660/1,614,142 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.57%	175
Finnishnot grpmax-eligible	0.358%	280
Remaining individualsnot grpmax-eligible	0.0432%	2,315
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0112%	8,940
South Asian	0.011%	9,108
African / African-American	0.004%	25,014
Admixed American	0.00333%	30,005

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.Arg875Trp
Coding: c.2623C>T
MANE Select: NM_198834
dbSNP: rs2287351
Type: single nucleotide variant
Location: chr17:37244707 (GRCh38)
Gene constraint: LOEUF 0.374 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 10 PDB
Residue 875: a turn

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

Similar variants

ACACA p.Arg875= Likely benign ★ same residue
ACACA p.Ala2308Val Uncertain significance ★★ ⚠ same type
ACACA p.Arg1206His Uncertain significance ★★ ⚠ same type
ACACA p.Arg2198Gln Uncertain significance ★★ ⚠ same type
ACACA p.Arg745Trp Uncertain significance ★★ ⚠ same type
ACACA p.Asn1903Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn728Ser Uncertain significance ★★ ⚠ same type
ACACA p.Asn950Ser 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-arg875trp (accessed [today's date]).

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