Is ARVCF p.Ser8Pro (c.22T>C) pathogenic?

ARVCF p.Ser8Pro (c.22T>C) is classified Uncertain significance in ARVCF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-25). AlphaMissense: ambiguous (0.4694); Ultra-rare (popmax 0.014%, eas).

How common is ARVCF p.Ser8Pro (c.22T>C) in the general population?

ARVCF p.Ser8Pro (c.22T>C) is ultra-rare (popmax 0.014%, eas) (gnomAD).

What do computational predictors say about ARVCF p.Ser8Pro (c.22T>C)?

AlphaMissense predicts ambiguous (score 0.4694) — an in-silico prediction, not a clinical call.

ARVCF p.Ser8Pro

c.22T>C · VCV3316866

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4694	ambiguous
REVEL	0.255	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 20 kb · p 0.02 · regional, not allelic
Overall
CADD	26.1	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 0.014% East Asian · 6/42,748 alleles

Filtering AF 0.00603% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0041%

Overall 0.000381% 6/1,575,566 alleles · ultra-rare exomes 5/1,423,330 · genomes 1/152,236 · joint denominator

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.Ser8Pro
Coding: c.22T>C
MANE Select: NM_001670
Type: single nucleotide variant
Location: chr22:19990773 (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.Ser8Leu Uncertain significance ★ ⚠ same residue
ARVCF p.Ser8Trp Uncertain significance ★ ⚠ same residue
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

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-ser8pro (accessed [today's date]).

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