Is ARVCF p.Arg417Trp (c.1249C>T) pathogenic?

ARVCF p.Arg417Trp (c.1249C>T) is classified Uncertain significance in ARVCF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.3619); Very rare (popmax 0.00535%, afr).

How common is ARVCF p.Arg417Trp (c.1249C>T) in the general population?

ARVCF p.Arg417Trp (c.1249C>T) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about ARVCF p.Arg417Trp (c.1249C>T)?

AlphaMissense predicts ambiguous (score 0.3619) — an in-silico prediction, not a clinical call.

ARVCF p.Arg417Trp

c.1249C>T · rs371292422 · VCV2617149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Computational evidence

Protein change
AlphaMissense	0.3619	ambiguous
REVEL	0.412	indeterminate
SaProt	LLR -7.16	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.02 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,752 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000935% 15/1,603,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,688
Remaining individualsnot grpmax-eligible	0.00323%	31,000
Admixed American	0.00169%	59,002
European (non-Finnish)	0.00068%	147,035

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.Arg417Trp
Coding: c.1249C>T
MANE Select: NM_001670
dbSNP: rs371292422
Type: single nucleotide variant
Location: chr22:19979890 (GRCh38)
Gene constraint: LOEUF 1.032 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.73

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-arg417trp (accessed [today's date]).

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