Is CAVIN1 p.Pro22Leu (c.65C>T) pathogenic?

CAVIN1 p.Pro22Leu (c.65C>T) is classified Conflicting classifications of pathogenicity in CAVIN1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.087); Rare (popmax 0.287%, afr); Associated with monogenic diabetes.

What condition is associated with CAVIN1 p.Pro22Leu (c.65C>T)?

CAVIN1 p.Pro22Leu (c.65C>T) is associated with monogenic diabetes, congenital generalized lipodystrophy type 4 (ClinVar).

How common is CAVIN1 p.Pro22Leu (c.65C>T) in the general population?

CAVIN1 p.Pro22Leu (c.65C>T) is rare (popmax 0.287%, afr) (gnomAD).

What do computational predictors say about CAVIN1 p.Pro22Leu (c.65C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

CAVIN1 p.Pro22Leu

c.65C>T · rs61729285 · VCV549548

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.287%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -7.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.76, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 18 kb · p 0.076 · regional, not allelic
Overall
CADD	17.64	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 0.287% African / African-American · 215/74,968 alleles

Filtering AF 0.255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.243%

Overall 0.02% 322/1,611,430 alleles · rare exomes 168/1,459,160 · genomes 154/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.287%	349
Remaining individualsnot grpmax-eligible	0.0737%	1,356
Admixed American	0.0686%	1,458
Middle Eastern	0.0335%	2,986
South Asian	0.011%	9,091
European (non-Finnish)	0.000678%	147,409

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: CAVIN1
Protein: p.Pro22Leu
Coding: c.65C>T
MANE Select: NM_012232
dbSNP: rs61729285
Type: single nucleotide variant
Location: chr17:42423033 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.03 · 3 PDB
Residue 22: the 'required for homotrimerization and for interaction with cavin2 and cavin3' region; the 'disordered' region

Full CAVIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

monogenic diabetes — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital generalized lipodystrophy type 4

Similar variants

CAVIN1 c.*1110C>T Uncertain significance ★★ same condition
CAVIN1 c.*195C>G Uncertain significance ★★ same condition
CAVIN1 p.Ala21Val Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Arg227Trp Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Leu172Val Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Pro283Ser Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Thr279Arg Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Val306Ala Uncertain significance ★★ ⚠ same condition

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/cavin1-p-pro22leu (accessed [today's date]).

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