Is CAVIN4 p.Pro228Leu (c.683C>T) pathogenic?

CAVIN4 p.Pro228Leu (c.683C>T) is classified Uncertain significance in CAVIN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-30). AlphaMissense: ambiguous (0.4586); Very rare (popmax 0.00533%, afr).

How common is CAVIN4 p.Pro228Leu (c.683C>T) in the general population?

CAVIN4 p.Pro228Leu (c.683C>T) is very rare (popmax 0.00533%, afr) (gnomAD).

What do computational predictors say about CAVIN4 p.Pro228Leu (c.683C>T)?

AlphaMissense predicts ambiguous (score 0.4586) — an in-silico prediction, not a clinical call.

CAVIN4 p.Pro228Leu

c.683C>T · rs144516649 · VCV1303314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00533%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4586	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,304 bp · p 0.38 · regional, not allelic
Overall
CADD	28.8	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 0.00533% African / African-American · 4/74,996 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00242% 39/1,614,064 alleles · very rare exomes 32/1,461,880 · genomes 7/152,184 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00533%	18,749
South Asian	0.00329%	30,353
European (non-Finnish)	0.00271%	36,875

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: CAVIN4
Protein: p.Pro228Leu
Coding: c.683C>T
MANE Select: NM_001018116
dbSNP: rs144516649
Type: single nucleotide variant
Location: chr9:100586039 (GRCh38)
Gene constraint: LOEUF 0.875 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 66.21

Full CAVIN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CAVIN4 p.Pro228Ala Uncertain significance ★ ⚠ same residue
CAVIN4 p.Pro228= Likely benign ★ same residue
CAVIN4 p.Arg17Cys Uncertain significance ★★ ⚠ same type
CAVIN4 p.Arg272Cys Uncertain significance ★★ ⚠ same type
CAVIN4 p.Asn128Lys Uncertain significance ★★ ⚠ same type
CAVIN4 p.Pro142Leu Uncertain significance ★★ ⚠ same type
CAVIN4 p.Ser20Thr Uncertain significance ★★ ⚠ same type
CAVIN4 c.408+28T>C Likely 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/cavin4-p-pro228leu (accessed [today's date]).

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