Is ACACA p.Arg1206His (c.3617G>A) pathogenic?

ACACA p.Arg1206His (c.3617G>A) is classified Uncertain significance in ACACA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1407); Ultra-rare (popmax 0.0733%, amr).

How common is ACACA p.Arg1206His (c.3617G>A) in the general population?

ACACA p.Arg1206His (c.3617G>A) is ultra-rare (popmax 0.0733%, amr) (gnomAD).

What do computational predictors say about ACACA p.Arg1206His (c.3617G>A)?

AlphaMissense predicts likely benign (score 0.1407) — an in-silico prediction, not a clinical call.

ACACA p.Arg1206His

c.3617G>A · rs763968366 · VCV3022505

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1407 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0733%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1407	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -7.96	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 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 42 bp · p 0.38 · regional, not allelic
Overall
CADD	25.5	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 R1169H vs ClinVar R1206H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0733% Admixed American · 44/59,994 alleles

Filtering AF 0.0561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0501%

Overall 0.00489% 79/1,614,018 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0733%	1,363
African / African-American	0.00534%	18,727
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00229%	43,704
East Asian	0.00223%	44,890

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.Arg1206His
Coding: c.3617G>A
MANE Select: NM_198834
dbSNP: rs763968366
Type: single nucleotide variant
Location: chr17:37221790 (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

Similar variants

ACACA p.Ala2308Val 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
ACACA p.Asp2228Asn Uncertain significance ★★ ⚠ same type
ACACA p.Gln2122His 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-arg1206his (accessed [today's date]).

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