Is ARRDC3 p.Arg414His (c.1241G>A) pathogenic?

ARRDC3 p.Arg414His (c.1241G>A) is classified Uncertain significance in ARRDC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1966); Ultra-rare (popmax 0.0352%, sas).

How common is ARRDC3 p.Arg414His (c.1241G>A) in the general population?

ARRDC3 p.Arg414His (c.1241G>A) is ultra-rare (popmax 0.0352%, sas) (gnomAD).

What do computational predictors say about ARRDC3 p.Arg414His (c.1241G>A)?

AlphaMissense predicts likely benign (score 0.1966) — an in-silico prediction, not a clinical call.

ARRDC3 p.Arg414His

c.1241G>A · rs769484237 · VCV2387656

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1966 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0352%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1966	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -6.59	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 2.2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 12 kb · p 4.7e-08 · regional, not allelic
Overall
CADD	28.2	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 0.0352% South Asian · 32/91,016 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.00298% 48/1,612,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0352%	2,844
Ashkenazi Jewishnot grpmax-eligible	0.0135%	7,395
Admixed American	0.00668%	14,977
European (non-Finnish)	0.000678%	147,416

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: ARRDC3
Protein: p.Arg414His
Coding: c.1241G>A
MANE Select: NM_020801
dbSNP: rs769484237
Type: single nucleotide variant
Location: chr5:91371404 (GRCh38)
Gene constraint: LOEUF 0.325 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 82.36 · 3 PDB
Residue 414: the 'disordered' region

Full ARRDC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRDC3 p.Arg414Cys Uncertain significance ★ ⚠ same residue
ARRDC3 p.Ala227Thr Uncertain significance ★ ⚠ same type
ARRDC3 p.Ala65Thr Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg109Gly Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg135His Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg284His Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg43Ser Uncertain significance ★ ⚠ same type
ARRDC3 p.Arg93Ile 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/arrdc3-p-arg414his (accessed [today's date]).

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