Is ARRDC5 p.Glu219Lys (c.655G>A) pathogenic?

ARRDC5 p.Glu219Lys (c.655G>A) is classified Uncertain significance in ARRDC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.0866); Very rare (popmax 0.00988%, sas).

How common is ARRDC5 p.Glu219Lys (c.655G>A) in the general population?

ARRDC5 p.Glu219Lys (c.655G>A) is very rare (popmax 0.00988%, sas) (gnomAD).

What do computational predictors say about ARRDC5 p.Glu219Lys (c.655G>A)?

AlphaMissense predicts likely benign (score 0.0866) — an in-silico prediction, not a clinical call.

ARRDC5 p.Glu219Lys

c.655G>A · rs372235175 · VCV3129871

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0866 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00988%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0866	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	LLR -6.27	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 -1.2	GERP -5.3
Regional constraint	o/e 0.97	unconstrained · MANE · 12 kb · p 0.54 · regional, not allelic
Overall
CADD	1.272	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM E233K vs ClinVar E219K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00988% South Asian · 9/91,090 alleles

Filtering AF 0.00514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00375%

Overall 0.000992% 16/1,613,410 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00988%	10,121
Admixed American	0.005%	19,985
African / African-American	0.00133%	74,916
European (non-Finnish)	0.000254%	393,295

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.Glu219Lys
Coding: c.655G>A
MANE Select: NM_001080523
dbSNP: rs372235175
Type: single nucleotide variant
Location: chr19:4891378 (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-glu219lys (accessed [today's date]).

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