Is CFAP69 p.Phe258Leu (c.774T>A) pathogenic?

CFAP69 p.Phe258Leu (c.774T>A) is classified Uncertain significance in CFAP69 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.9681); Very rare (popmax 0.00772%, sas).

How common is CFAP69 p.Phe258Leu (c.774T>A) in the general population?

CFAP69 p.Phe258Leu (c.774T>A) is very rare (popmax 0.00772%, sas) (gnomAD).

What do computational predictors say about CFAP69 p.Phe258Leu (c.774T>A)?

AlphaMissense predicts likely pathogenic (score 0.9681) — an in-silico prediction, not a clinical call.

CFAP69 p.Phe258Leu

c.774T>A · VCV4001620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00772%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9681	likely pathogenic · top 1% in CFAP69
REVEL	0.208	benign-leaning
SaProt	LLR -5.13	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 4.5, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 65 kb · p 0.37 · regional, not allelic
Overall
CADD	23.9	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 0.00772% South Asian · 7/90,618 alleles

Filtering AF 0.0036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00256%

Overall 0.00048% 7/1,458,630 alleles · very rare

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: CFAP69
Protein: p.Phe258Leu
Coding: c.774T>A
MANE Select: NM_001039706
Type: single nucleotide variant
Location: chr7:90271872 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.48
Residue 258: a UniProt-annotated variant site (in spgf24)

Full CFAP69 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP69 p.Phe731Leu Uncertain significance ★★ ⚠ same type
CFAP69 p.Tyr819His Uncertain significance ★★ ⚠ same type
CFAP69 c.1857+47T>A Benign ★★ same type
CFAP69 c.682+50A>C Benign ★★ same type
CFAP69 p.Ala12= Benign ★★ same type
CFAP69 p.Ala182= Benign ★★ same type
CFAP69 p.Ala8= Benign/Likely benign ★★ same type
CFAP69 p.Arg106His 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/cfap69-p-phe258leu (accessed [today's date]).

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