Is ACCS p.Arg434Cys (c.1300C>T) pathogenic?

ACCS p.Arg434Cys (c.1300C>T) is classified Uncertain significance in ACCS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0895); Ultra-rare (popmax 0.03%, amr).

How common is ACCS p.Arg434Cys (c.1300C>T) in the general population?

ACCS p.Arg434Cys (c.1300C>T) is ultra-rare (popmax 0.03%, amr) (gnomAD).

What do computational predictors say about ACCS p.Arg434Cys (c.1300C>T)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

ACCS p.Arg434Cys

c.1300C>T · rs375801245 · VCV2468915

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -10.28	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.092	GERP -2.1
Regional constraint	o/e 0.95	unconstrained · MANE · 16 kb · p 0.26 · regional, not allelic
Overall
CADD	16.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,002 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00248% 40/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,333
African / African-American	0.0227%	4,408
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0011%	91,094
European (non-Finnish)	0.000169%	590,023

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.Arg434Cys
Coding: c.1300C>T
MANE Select: NM_032592
dbSNP: rs375801245
Type: single nucleotide variant
Location: chr11:44083469 (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.Arg434His Uncertain significance ★ ⚠ same residue
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

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-arg434cys (accessed [today's date]).

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