Is CFI p.Phe139Val (c.415T>G) pathogenic?

CFI p.Phe139Val (c.415T>G) is classified Uncertain significance in CFI (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-11). AlphaMissense: likely benign (0.2861); Ultra-rare (popmax 0.0483%, amr).

How common is CFI p.Phe139Val (c.415T>G) in the general population?

CFI p.Phe139Val (c.415T>G) is ultra-rare (popmax 0.0483%, amr) (gnomAD).

What do computational predictors say about CFI p.Phe139Val (c.415T>G)?

AlphaMissense predicts likely benign (score 0.2861) — an in-silico prediction, not a clinical call.

CFI p.Phe139Val

c.415T>G · rs751034950 · VCV1403534

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2861 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2861	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 0.62, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	22.8	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 0.0483% Admixed American · 29/59,998 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0018% 29/1,614,076 alleles · ultra-rare exomes 28/1,461,858 · genomes 1/152,218 · joint denominator

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.Phe139Val
Coding: c.415T>G
MANE Select: NM_000204
dbSNP: rs751034950
Type: single nucleotide variant
Location: chr4:109764604 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 139: the srcr domain; a β-strand

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

Similar variants

CFI p.Phe139Leu Uncertain significance ★ ⚠ same residue
CFI p.Phe139Ser 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

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-phe139val (accessed [today's date]).

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