Is CAVIN4 p.Pro142Leu (c.425C>T) pathogenic?

CAVIN4 p.Pro142Leu (c.425C>T) is classified Uncertain significance in CAVIN4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.3234); Ultra-rare (popmax 0.0329%, mid).

How common is CAVIN4 p.Pro142Leu (c.425C>T) in the general population?

CAVIN4 p.Pro142Leu (c.425C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CAVIN4 p.Pro142Leu (c.425C>T)?

AlphaMissense predicts likely benign (score 0.3234) — an in-silico prediction, not a clinical call.

CAVIN4 p.Pro142Leu

c.425C>T · rs768645960 · VCV450258

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3234 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3234	likely benign
REVEL	0.594	indeterminate
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 8,304 bp · p 0.38 · regional, not allelic
Overall
CADD	27.8	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0031% 50/1,613,774 alleles · ultra-rare exomes 41/1,461,760 · genomes 9/152,014 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
African / African-American	0.0187%	5,348
South Asian	0.00988%	10,117
Finnishnot grpmax-eligible	0.00469%	21,317
European (non-Finnish)	0.00178%	56,188
Admixed American	0.00167%	59,982

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.Pro142Leu
Coding: c.425C>T
MANE Select: NM_001018116
dbSNP: rs768645960
Type: single nucleotide variant
Location: chr9:100585781 (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.Pro142Ala Uncertain significance ★ ⚠ 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.Ser20Thr Uncertain significance ★★ ⚠ same type
CAVIN4 c.408+28T>C Likely benign ★★ same type
CAVIN4 c.408+42T>C Benign ★★ same type
CAVIN4 c.408+6C>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/cavin4-p-pro142leu (accessed [today's date]).

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