Is CFAP74 p.Leu221Pro (c.662T>C) pathogenic?

CFAP74 p.Leu221Pro (c.662T>C) is classified Uncertain significance in CFAP74 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). AlphaMissense: likely pathogenic (0.7525); Very rare (popmax 0.00958%, nfe).

How common is CFAP74 p.Leu221Pro (c.662T>C) in the general population?

CFAP74 p.Leu221Pro (c.662T>C) is very rare (popmax 0.00958%, nfe) (gnomAD).

What do computational predictors say about CFAP74 p.Leu221Pro (c.662T>C)?

AlphaMissense predicts likely pathogenic (score 0.7525) — an in-silico prediction, not a clinical call.

CFAP74 p.Leu221Pro

c.662T>C · rs756378965 · VCV2528544

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7525 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00958%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7525	likely pathogenic · top 9% in CFAP74
REVEL	0.152	moderately benign-leaning
SaProt	LLR -12.36	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -3.5, phastCons 0.067
Regional constraint	o/e 1.02	unconstrained · MANE · 69 kb · p 0.48 · regional, not allelic
Overall
CADD	16.98	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 0.00958% European (non-Finnish) · 111/1,159,118 alleles

Filtering AF 0.00805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00757%

Overall 0.00753% 119/1,580,444 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00958%	10,443
Admixed American	0.00527%	18,986
Remaining individualsnot grpmax-eligible	0.00493%	20,265
East Asian	0.0023%	43,446
African / African-American	0.00135%	73,966

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: CFAP74
Protein: p.Leu221Pro
Coding: c.662T>C
MANE Select: NM_001304360
dbSNP: rs756378965
Type: single nucleotide variant
Location: chr1:1974037 (GRCh38)
Gene constraint: LOEUF 0.799 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.38

Full CFAP74 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP74 p.Lys394Met Uncertain significance ★★ ⚠ same type
CFAP74 p.Arg365Gln Likely benign ★★ same type
CFAP74 p.Gly5Ser Likely benign ★★ same type
CFAP74 p.Arg280Ter Likely pathogenic ★ same type
CFAP74 c.1851+2T>C Uncertain significance ★ same type
CFAP74 c.2176+30T>G Uncertain significance ★ same type
CFAP74 c.2176+34C>T Uncertain significance ★ same type
CFAP74 c.785+1G>A Uncertain significance ★ 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/cfap74-p-leu221pro (accessed [today's date]).

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