Is CFAP251 p.Ile699Val (c.2095A>G) pathogenic?

CFAP251 p.Ile699Val (c.2095A>G) is classified Uncertain significance in CFAP251 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely benign (0.0698); Ultra-rare (popmax 0.0101%, nfe).

How common is CFAP251 p.Ile699Val (c.2095A>G) in the general population?

CFAP251 p.Ile699Val (c.2095A>G) is ultra-rare (popmax 0.0101%, nfe) (gnomAD).

What do computational predictors say about CFAP251 p.Ile699Val (c.2095A>G)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

CFAP251 p.Ile699Val

c.2095A>G · rs753450280 · VCV2521991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0101%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -5.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.45	donor loss · deltas
Pangolin	Δ0.41	gain · loss 0.10 · SpliceAI calls loss · independent
Constraint at this position
Conservation	phyloP 1.4	GERP 0.3, phastCons 0.23
Regional constraint	o/e 0.93	unconstrained · MANE · 82 kb · p 0.0061 · regional, not allelic
Overall
CADD	9.206	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 0.0101% European (non-Finnish) · 119/1,178,914 alleles

Filtering AF 0.0086% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00804%

Overall 0.00801% 129/1,609,594 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0145%	6,918
European (non-Finnish)grpmax	0.0101%	9,907
African / African-American	0.00134%	74,602

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile699Val
Coding: c.2095A>G
MANE Select: NM_144668
dbSNP: rs753450280
Type: single nucleotide variant
Location: chr12:121959056 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.84 · 1 PDB
Residue 699: a UniProt-annotated variant site (in spgf33)

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

Similar variants

CFAP251 p.Arg267Ter Pathogenic ★★ same type
CFAP251 p.Glu111Ter Pathogenic/Likely pathogenic ★★ same type
CFAP251 c.-20-20T>C Benign ★★ same type
CFAP251 p.Arg417Gln Benign ★★ same type
CFAP251 p.Ile970= Likely benign ★★ same type
CFAP251 p.Val307Ile Benign ★★ ⚠ same type
CFAP251 c.-20-2A>C Likely pathogenic ★ same type
CFAP251 p.Gln129Ter Likely pathogenic ★ 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/cfap251-p-ile699val (accessed [today's date]).

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