Is CFAP221 p.Val280Ile (c.838G>A) pathogenic?

CFAP221 p.Val280Ile (c.838G>A) is classified Benign in CFAP221 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: likely benign (0.0685); Low-frequency (popmax 1.34%, nfe).

How common is CFAP221 p.Val280Ile (c.838G>A) in the general population?

CFAP221 p.Val280Ile (c.838G>A) is low-frequency (popmax 1.34%, nfe) (gnomAD).

What do computational predictors say about CFAP221 p.Val280Ile (c.838G>A)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

CFAP221 p.Val280Ile

c.838G>A · rs61741340 · VCV2651305

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.34%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.004	strongly benign-leaning
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -2.1	GERP -3.7
Regional constraint	o/e 1.01	unconstrained · MANE · 110 kb · p 0.72 · regional, not allelic
Overall
CADD	0.075	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 1.34% European (non-Finnish) · 15,457/1,154,164 alleles

Filtering AF 1.32% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.31%

Overall 1.1% 17,074/1,551,400 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.43%	70
European (non-Finnish)grpmax	1.34%	75
Admixed American	1.11%	90
Remaining individualsnot grpmax-eligible	0.812%	123
Finnishnot grpmax-eligible	0.386%	259
African / African-American	0.236%	423
South Asian	0.233%	430
Middle Eastern	0.174%	574
Ashkenazi Jewishnot grpmax-eligible	0.057%	1,755

Amish 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: CFAP221
Protein: p.Val280Ile
Coding: c.838G>A
MANE Select: NM_001271049
dbSNP: rs61741340
Type: single nucleotide variant
Location: chr2:119604718 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.53

Full CFAP221 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CFAP221 p.Arg131Ter Pathogenic ★ same type
CFAP221 c.1025-1G>A Uncertain significance ★ same type
CFAP221 p.Asn834Asp Uncertain significance ★ same type
CFAP221 p.Ile567Asn Uncertain significance ★ ⚠ same type
CFAP221 p.Leu833Phe Uncertain significance ★ ⚠ same type
CFAP221 c.1311+7A>G Likely benign ★ same type
CFAP221 c.632-7C>G Likely benign ★ same type
CFAP221 p.Arg433Cys Likely 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/cfap221-p-val280ile (accessed [today's date]).

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