Is ARRDC5 p.Thr201Ile (c.602C>T) pathogenic?

ARRDC5 p.Thr201Ile (c.602C>T) is classified Uncertain significance in ARRDC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely pathogenic (0.8441); Ultra-rare (popmax 0.0509%, nfe).

How common is ARRDC5 p.Thr201Ile (c.602C>T) in the general population?

ARRDC5 p.Thr201Ile (c.602C>T) is ultra-rare (popmax 0.0509%, nfe) (gnomAD).

What do computational predictors say about ARRDC5 p.Thr201Ile (c.602C>T)?

AlphaMissense predicts likely pathogenic (score 0.8441) — an in-silico prediction, not a clinical call.

ARRDC5 p.Thr201Ile

c.602C>T · rs199680732 · VCV2510900

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8441 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8441	likely pathogenic · top 7% in ARRDC5
REVEL	0.244	benign-leaning
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 12 kb · p 0.54 · regional, not allelic
Overall
CADD	25.4	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 T215I vs ClinVar T201I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0509% European (non-Finnish) · 600/1,179,914 alleles

Filtering AF 0.0475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0461%

Overall 0.041% 661/1,613,400 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0512%	1,952
European (non-Finnish)grpmax	0.0509%	1,967
Finnishnot grpmax-eligible	0.0283%	3,530
African / African-American	0.012%	8,326
Admixed American	0.00333%	29,985

Remaining individuals 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: ARRDC5
Protein: p.Thr201Ile
Coding: c.602C>T
MANE Select: NM_001080523
dbSNP: rs199680732
Type: single nucleotide variant
Location: chr19:4891431 (GRCh38)
Gene constraint: LOEUF 1.342 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.19

Full ARRDC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRDC5 c.-15A>T Uncertain significance ★ ⚠ same type
ARRDC5 c.-24T>C Uncertain significance ★ ⚠ same type
ARRDC5 p.Ala241Val Uncertain significance ★ ⚠ same type
ARRDC5 p.Ala305Asp Uncertain significance ★ ⚠ same type
ARRDC5 p.Ala305Thr Uncertain significance ★ ⚠ same type
ARRDC5 p.Ala90Ser Uncertain significance ★ ⚠ same type
ARRDC5 p.Arg135Gly Uncertain significance ★ ⚠ same type
ARRDC5 p.Arg227Trp 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/arrdc5-p-thr201ile (accessed [today's date]).

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