Is ACCS p.Arg433His (c.1298G>A) pathogenic?

ACCS p.Arg433His (c.1298G>A) is classified Uncertain significance in ACCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0165%, mid).

How common is ACCS p.Arg433His (c.1298G>A) in the general population?

ACCS p.Arg433His (c.1298G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ACCS p.Arg433His (c.1298G>A)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

ACCS p.Arg433His

c.1298G>A · VCV4215181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -8.45	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.81	GERP 0.65, phastCons 0.19
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.26 · regional, not allelic
Overall
CADD	20.9	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00626% 101/1,614,206 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.0156%	6,411
Admixed American	0.0133%	7,503
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	0.00576%	17,353
African / African-American	0.00266%	37,530
Finnishnot grpmax-eligible	0.00156%	64,042
South Asian	0.0011%	91,082

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ACCS
Protein: p.Arg433His
Coding: c.1298G>A
MANE Select: NM_032592
Type: single nucleotide variant
Location: chr11:44083467 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.63

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

Similar variants

ACCS p.Arg489Cys Benign ★★ same type
ACCS p.Val202= Benign ★★ same type
ACCS p.Ala11Val Uncertain significance ★ ⚠ same type
ACCS p.Ala237Thr Uncertain significance ★ ⚠ same type
ACCS p.Ala77Ser Uncertain significance ★ ⚠ same type
ACCS p.Arg124Lys Uncertain significance ★ ⚠ same type
ACCS p.Arg142Gln Uncertain significance ★ ⚠ same type
ACCS p.Arg142Trp 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/accs-p-arg433his (accessed [today's date]).

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