Is CFI p.Met138Val (c.412A>G) pathogenic?

CFI p.Met138Val (c.412A>G) is classified Likely pathogenic in CFI (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely benign (0.0814); Ultra-rare (popmax 0.0329%, mid); Associated with CFI-related disorder.

What condition is associated with CFI p.Met138Val (c.412A>G)?

CFI p.Met138Val (c.412A>G) is associated with CFI-related disorder (ClinVar).

How common is CFI p.Met138Val (c.412A>G) in the general population?

CFI p.Met138Val (c.412A>G) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about CFI p.Met138Val (c.412A>G)?

AlphaMissense predicts likely benign (score 0.0814) — an in-silico prediction, not a clinical call.

CFI p.Met138Val

c.412A>G · VCV4280515

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CFI-related disorder

Computational evidence

Protein change
AlphaMissense	0.0814	likely benign ⚠ discordant with ClinVar
REVEL	0.304	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.75	GERP -2.7, phastCons 0.006
Regional constraint	o/e 1.00	unconstrained · MANE · 61 kb · p 0.95 · regional, not allelic
Overall
CADD	5.722	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000186% 3/1,614,000 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
South Asian	0.0011%	91,088

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.Met138Val
Coding: c.412A>G
MANE Select: NM_000204
Type: single nucleotide variant
Location: chr4:109764607 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.50 · 2 PDB
Residue 138: a disulfide bond; the srcr domain; a β-strand

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

Disease context

CFI-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFI p.Met138Ile Uncertain significance ★ same residue
CFI p.Arg187Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Arg474Ter Pathogenic/Likely pathogenic ★★ same condition
CFI p.Met138fs Pathogenic/Likely pathogenic ★★ same residue
CFI p.Trp145Ter Pathogenic ★★ same condition
CFI p.Ala153Thr Uncertain significance ★★ ⚠ same condition
CFI p.Ala76Gly Uncertain significance ★★ ⚠ same condition
CFI p.Arg317Gln Uncertain significance ★★ ⚠ same condition

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-met138val (accessed [today's date]).

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