Is ARRDC4 p.Ala77= (c.231C>T) pathogenic?

ARRDC4 p.Ala77= (c.231C>T) is classified Benign in ARRDC4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-05-11). Common (popmax 30.8%, nfe) — too common for a highly-penetrant pathogenic allele.

ARRDC4 p.Ala77=

Q: How common is ARRDC4 p.Ala77= (c.231C>T) in the general population?

ARRDC4 p.Ala77= (c.231C>T) is common (popmax 30.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.231C>T · rs112100339 · VCV1231421

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 30.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.5	GERP 0.23
Overall
CADD	3.588	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.8% European (non-Finnish) · 340,013/1,104,556 alleles

Filtering AF 30.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 30.7%

Overall 28.6% 412,551/1,442,820 alleles · common exomes 379,418/1,291,178 · genomes 33,133/151,642 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	36.6%	3
Amishnot grpmax-eligible	32.9%	3
European (non-Finnish)grpmax	30.8%	3
Middle Eastern	30.3%	3
Finnishnot grpmax-eligible	28.3%	4
Remaining individualsnot grpmax-eligible	27.7%	4
South Asian	26.8%	4
Admixed American	22.1%	5
East Asian	9.1%	11
African / African-American	5.37%	19

Ashkenazi Jewish 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: ARRDC4
Protein: p.Ala77=
Coding: c.231C>T
MANE Select: NM_183376
dbSNP: rs112100339
Type: single nucleotide variant
Location: chr15:97961092 (GRCh38)
Gene constraint: LOEUF 1.309 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.38

Full ARRDC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARRDC4 p.Thr79Ala Benign ★★ same type
ARRDC4 p.Ala211Thr Uncertain significance ★ ⚠ same type
ARRDC4 p.Ala252Thr Uncertain significance ★ ⚠ same type
ARRDC4 p.Ala294Ser Uncertain significance ★ ⚠ same type
ARRDC4 p.Ala9Thr Uncertain significance ★ ⚠ same type
ARRDC4 p.Arg119Cys Uncertain significance ★ ⚠ same type
ARRDC4 p.Arg143Trp Uncertain significance ★ ⚠ same type
ARRDC4 p.Arg158Gln 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/arrdc4-p-ala77 (accessed [today's date]).

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