Is ARVCF p.Pro230Arg (c.689C>G) pathogenic?

ARVCF p.Pro230Arg (c.689C>G) is classified Uncertain significance in ARVCF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-02). AlphaMissense: likely benign (0.1907); Ultra-rare (popmax 0.0349%, amr).

How common is ARVCF p.Pro230Arg (c.689C>G) in the general population?

ARVCF p.Pro230Arg (c.689C>G) is ultra-rare (popmax 0.0349%, amr) (gnomAD).

What do computational predictors say about ARVCF p.Pro230Arg (c.689C>G)?

AlphaMissense predicts likely benign (score 0.1907) — an in-silico prediction, not a clinical call.

ARVCF p.Pro230Arg

c.689C>G · VCV4643252

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0349%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1907	likely benign
REVEL	0.344	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.02 · regional, not allelic
Overall
CADD	26.3	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 0.0349% Admixed American · 19/54,436 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.019%

Overall 0.00406% 64/1,576,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0349%	2,865
Remaining individualsnot grpmax-eligible	0.0131%	7,614
European (non-Finnish)	0.00318%	31,449

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: ARVCF
Protein: p.Pro230Arg
Coding: c.689C>G
MANE Select: NM_001670
Type: single nucleotide variant
Location: chr22:19981418 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.73
Residue 230: the 'disordered' region

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

Similar variants

ARVCF p.Gly172Ser Uncertain significance ★★ ⚠ same type
ARVCF p.Val958Ile Uncertain significance ★★ ⚠ same type
ARVCF c.1396+18A>G Benign ★★ same type
ARVCF c.1396+198C>T Benign ★★ same type
ARVCF c.1396+40G>A Benign ★★ same type
ARVCF c.1397-146G>A Benign ★★ same type
ARVCF c.1397-7C>T Benign ★★ same type
ARVCF c.1871-172A>C Benign ★★ 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/arvcf-p-pro230arg (accessed [today's date]).

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