Is ARVCF p.Pro353Ser (c.1057C>T) pathogenic?

ARVCF p.Pro353Ser (c.1057C>T) is classified Uncertain significance in ARVCF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely benign (0.2844); Very rare (popmax 0.00343%, nfe).

How common is ARVCF p.Pro353Ser (c.1057C>T) in the general population?

ARVCF p.Pro353Ser (c.1057C>T) is very rare (popmax 0.00343%, nfe) (gnomAD).

What do computational predictors say about ARVCF p.Pro353Ser (c.1057C>T)?

AlphaMissense predicts likely benign (score 0.2844) — an in-silico prediction, not a clinical call.

ARVCF p.Pro353Ser

c.1057C>T · VCV4643271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00343%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2844	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -8.90	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.2	GERP 0.41, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.02 · regional, not allelic
Overall
CADD	23.6	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 0.00343% European (non-Finnish) · 40/1,165,642 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00259% 41/1,582,316 alleles · very rare exomes 39/1,430,106 · genomes 2/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00343%	29,141
Remaining individualsnot grpmax-eligible	0.00164%	60,992

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.Pro353Ser
Coding: c.1057C>T
MANE Select: NM_001670
Type: single nucleotide variant
Location: chr22:19980082 (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-pro353ser (accessed [today's date]).

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