Is ARVCF p.Ala14Pro (c.40G>C) pathogenic?

ARVCF p.Ala14Pro (c.40G>C) is classified Uncertain significance in ARVCF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely pathogenic (0.9767); Very rare (popmax 0.0072%, nfe).

How common is ARVCF p.Ala14Pro (c.40G>C) in the general population?

ARVCF p.Ala14Pro (c.40G>C) is very rare (popmax 0.0072%, nfe) (gnomAD).

What do computational predictors say about ARVCF p.Ala14Pro (c.40G>C)?

AlphaMissense predicts likely pathogenic (score 0.9767) — an in-silico prediction, not a clinical call.

ARVCF p.Ala14Pro

c.40G>C · rs200353808 · VCV2377368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9767 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0072%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9767	likely pathogenic · top 10% in ARVCF
REVEL	0.24	benign-leaning
SaProt	LLR -14.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.02 · regional, not allelic
Overall
CADD	29.2	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 0.0072% European (non-Finnish) · 84/1,166,316 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00547%

Overall 0.00554% 88/1,587,396 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0072%	13,885
Remaining individualsnot grpmax-eligible	0.00326%	30,681
African / African-American	0.00269%	37,180

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.Ala14Pro
Coding: c.40G>C
MANE Select: NM_001670
dbSNP: rs200353808
Type: single nucleotide variant
Location: chr22:19990755 (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-ala14pro (accessed [today's date]).

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