Is CFAP251 p.Leu445Phe (c.1333C>T) pathogenic?

CFAP251 p.Leu445Phe (c.1333C>T) is classified Benign in CFAP251 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2019-10-21). AlphaMissense: likely benign (0.1576); Common (popmax 56.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CFAP251-related disorder.

What condition is associated with CFAP251 p.Leu445Phe (c.1333C>T)?

CFAP251 p.Leu445Phe (c.1333C>T) is associated with CFAP251-related disorder (ClinVar).

What do computational predictors say about CFAP251 p.Leu445Phe (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.1576) — an in-silico prediction, not a clinical call.

CFAP251 p.Leu445Phe

Q: How common is CFAP251 p.Leu445Phe (c.1333C>T) in the general population?

CFAP251 p.Leu445Phe (c.1333C>T) is common (popmax 56.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1333C>T · rs11043265 · VCV3060409

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1576 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 56.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFAP251-related disorder

Computational evidence

Protein change
AlphaMissense	0.1576	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -6.78	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 4.9	GERP 0.84, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 82 kb · p 0.0061 · regional, not allelic
Overall
CADD	20.0	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 56.4% African / African-American · 42,250/74,856 alleles

Filtering AF 56% ClinGen BA1/BS1 input FAF95, joint · FAF99 55.8%

Overall 9.29% 149,850/1,613,332 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	56.4%	2
East Asian	28.8%	3
South Asian	27%	4
Middle Eastern	15.1%	7
Remaining individualsnot grpmax-eligible	11.5%	9
Admixed American	8.18%	12
Ashkenazi Jewishnot grpmax-eligible	4.58%	22
European (non-Finnish)	4.53%	22
Amishnot grpmax-eligible	3.95%	25
Finnishnot grpmax-eligible	3.46%	29

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: CFAP251
Protein: p.Leu445Phe
Coding: c.1333C>T
MANE Select: NM_144668
dbSNP: rs11043265
Type: single nucleotide variant
Location: chr12:121954132 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.84 · 1 PDB
Residue 445: a UniProt-annotated variant site (in spgf33); a UniProt-annotated variant site (in)

Full CFAP251 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CFAP251-related disorder

Similar variants

CFAP251 p.Arg267Ter Pathogenic ★★ same condition
CFAP251 c.2492+10C>G Likely benign same condition
CFAP251 p.Asn286= Benign same condition
CFAP251 p.Asp511= Likely benign same condition
CFAP251 p.Glu207= Likely benign same condition
CFAP251 p.Gly649= Likely benign same condition
CFAP251 p.His356= Benign same condition
CFAP251 p.His740= 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/cfap251-p-leu445phe (accessed [today's date]).

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