Is CCDC33 p.Leu658Phe (c.1972C>T) pathogenic?

CCDC33 p.Leu658Phe (c.1972C>T) is classified Uncertain significance in CCDC33 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-09). Very rare (popmax 0.00509%, nfe).

How common is CCDC33 p.Leu658Phe (c.1972C>T) in the general population?

CCDC33 p.Leu658Phe (c.1972C>T) is very rare (popmax 0.00509%, nfe) (gnomAD).

CCDC33 p.Leu658Phe

c.1972C>T · rs746751133 · VCV2276079

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00509%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.213	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 99 kb · p 0.88 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00509% European (non-Finnish) · 60/1,179,782 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.0039% 63/1,613,688 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00509%	19,663
Finnishnot grpmax-eligible	0.00313%	31,984
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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: CCDC33
Protein: p.Leu658Phe
Coding: c.1972C>T
MANE Select: NM_025055
dbSNP: rs746751133
Type: single nucleotide variant
Location: chr15:74333914 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.34

Full CCDC33 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CCDC33 p.Leu658His Uncertain significance ★ same residue
CCDC33 p.Pro610Leu Likely benign ★★ same type
STRA6 c.96+1744C>G Benign ★★ same type
STRA6 c.-15-751T>G Benign ★★ same type
STRA6 c.-16+1061C>G Likely benign ★★ same type
STRA6 c.-16+1161G>A Benign ★★ same type
STRA6 c.-16+794G>C Benign ★★ same type
STRA6 c.-5200G>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/ccdc33-p-leu658phe (accessed [today's date]).

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