Is ARRDC5 p.Glu43Lys (c.127G>A) pathogenic?

ARRDC5 p.Glu43Lys (c.127G>A) is classified Uncertain significance in ARRDC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely pathogenic (0.6315); Very rare (popmax 0.00932%, nfe).

How common is ARRDC5 p.Glu43Lys (c.127G>A) in the general population?

ARRDC5 p.Glu43Lys (c.127G>A) is very rare (popmax 0.00932%, nfe) (gnomAD).

What do computational predictors say about ARRDC5 p.Glu43Lys (c.127G>A)?

AlphaMissense predicts likely pathogenic (score 0.6315) — an in-silico prediction, not a clinical call.

ARRDC5 p.Glu43Lys

c.127G>A · VCV3432120

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6315 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00932%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6315	likely pathogenic
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 12 kb · p 0.54 · regional, not allelic
Overall
CADD	28.2	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 E57K vs ClinVar E43K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00932% European (non-Finnish) · 110/1,179,910 alleles

Filtering AF 0.00791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00736%

Overall 0.00706% 114/1,613,906 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00932%	10,726
Remaining individualsnot grpmax-eligible	0.0032%	31,233
Finnishnot grpmax-eligible	0.00156%	64,024
South Asian	0.0011%	91,092

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.Glu43Lys
Coding: c.127G>A
MANE Select: NM_001080523
Type: single nucleotide variant
Location: chr19:4902699 (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-glu43lys (accessed [today's date]).

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