Is ARRDC1 p.Ser433Thr (c.1298G>C) pathogenic?

ARRDC1 p.Ser433Thr (c.1298G>C) is classified Uncertain significance in ARRDC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-24). AlphaMissense: likely benign (0.0642); Very rare (popmax 8.77e-05%, nfe).

How common is ARRDC1 p.Ser433Thr (c.1298G>C) in the general population?

ARRDC1 p.Ser433Thr (c.1298G>C) is very rare (popmax 8.77e-05%, nfe) (gnomAD).

What do computational predictors say about ARRDC1 p.Ser433Thr (c.1298G>C)?

AlphaMissense predicts likely benign (score 0.0642) — an in-silico prediction, not a clinical call.

ARRDC1 p.Ser433Thr

c.1298G>C · rs1440004434 · VCV2470932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.77e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0642	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	LLR -6.95	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 3.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,417 bp · p 0.014 · regional, not allelic
Overall
CADD	18.87	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 8.77e-05% European (non-Finnish) · 1/1,140,566 alleles

Overall 7.22e-05% 1/1,384,580 alleles · very rare

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: ARRDC1
Protein: p.Ser433Thr
Coding: c.1298G>C
MANE Select: NM_152285
dbSNP: rs1440004434
Type: single nucleotide variant
Location: chr9:137615134 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.34

Full ARRDC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRDC1 p.Ala223Val Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala228Val Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala25Ser Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala285Thr Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala311Thr Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala34Val Uncertain significance ★ ⚠ same type
ARRDC1 p.Ala94Val Uncertain significance ★ ⚠ same type
ARRDC1 p.Arg119Gln 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/arrdc1-p-ser433thr (accessed [today's date]).

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