Is CAVIN1 p.Pro283Ser (c.847C>T) pathogenic?

CAVIN1 p.Pro283Ser (c.847C>T) is classified Uncertain significance in CAVIN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-14). AlphaMissense: likely benign (0.1598); Ultra-rare (popmax 0.0197%, nfe); Associated with congenital generalized lipodystrophy type 4.

What condition is associated with CAVIN1 p.Pro283Ser (c.847C>T)?

CAVIN1 p.Pro283Ser (c.847C>T) is associated with congenital generalized lipodystrophy type 4 (ClinVar).

How common is CAVIN1 p.Pro283Ser (c.847C>T) in the general population?

CAVIN1 p.Pro283Ser (c.847C>T) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

What do computational predictors say about CAVIN1 p.Pro283Ser (c.847C>T)?

AlphaMissense predicts likely benign (score 0.1598) — an in-silico prediction, not a clinical call.

CAVIN1 p.Pro283Ser

c.847C>T · rs367826339 · VCV2439771

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1598 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital generalized lipodystrophy type 4

Computational evidence

Protein change
AlphaMissense	0.1598	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -6.49	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 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 18 kb · p 0.076 · regional, not allelic
Overall
CADD	21.9	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 0.0197% European (non-Finnish) · 233/1,180,012 alleles

Filtering AF 0.0176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0148% 239/1,614,152 alleles · ultra-rare exomes 226/1,461,846 · genomes 13/152,306 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,064
Remaining individualsnot grpmax-eligible	0.0048%	20,833
African / African-American	0.004%	25,021

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.Pro283Ser
Coding: c.847C>T
MANE Select: NM_012232
dbSNP: rs367826339
Type: single nucleotide variant
Location: chr17:42405013 (GRCh38)
Gene constraint: LOEUF 1.092 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.03 · 3 PDB
Residue 283: the 'leucine-zipper 3' region

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

Disease context

congenital generalized lipodystrophy type 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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.Thr279Arg Uncertain significance ★★ ⚠ same condition
CAVIN1 p.Val306Ala Uncertain significance ★★ ⚠ same condition
CAVIN1 c.*104C>T Likely benign ★★ 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-pro283ser (accessed [today's date]).

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