Is CFI p.Val341Ala (c.1022T>C) pathogenic?

CFI p.Val341Ala (c.1022T>C) is classified Uncertain significance in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-19). AlphaMissense: ambiguous (0.5035); Very rare (popmax 0.00167%, amr).

How common is CFI p.Val341Ala (c.1022T>C) in the general population?

CFI p.Val341Ala (c.1022T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CFI p.Val341Ala (c.1022T>C)?

AlphaMissense predicts ambiguous (score 0.5035) — an in-silico prediction, not a clinical call.

CFI p.Val341Ala

c.1022T>C · rs747842653 · VCV1896803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5035	ambiguous
REVEL	0.67	pathogenic-leaning
SaProt	LLR -9.59	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 1.6, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	23.1	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 0.00167% Admixed American · 1/59,978 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,448 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,978
European (non-Finnish)	0.000339%	294,890

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: CFI
Protein: p.Val341Ala
Coding: c.1022T>C
MANE Select: NM_000204
dbSNP: rs747842653
Type: single nucleotide variant
Location: chr4:109749521 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 341: a disulfide bond; the peptidase s1 domain

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

Similar variants

CFI p.Val341Met Uncertain significance ★ ⚠ same residue
CFI c.1429+1G>C Pathogenic/Likely pathogenic ★★ same type
CFI c.57+1G>C Likely pathogenic ★★ same type
CFI c.658+1G>A Likely pathogenic ★★ same type
CFI c.905-1G>C Likely pathogenic ★★ same type
CFI p.Ala258Thr Pathogenic/Likely pathogenic ★★ ⚠ same type
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same type
CFI p.Arg474Ter Pathogenic/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/cfi-p-val341ala (accessed [today's date]).

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