Is FERMT2 p.Pro9Leu (c.26C>T) pathogenic?

FERMT2 p.Pro9Leu (c.26C>T) is classified Uncertain significance in FERMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-30). AlphaMissense: likely pathogenic (0.9432); Very rare (popmax 0.00667%, amr).

How common is FERMT2 p.Pro9Leu (c.26C>T) in the general population?

FERMT2 p.Pro9Leu (c.26C>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about FERMT2 p.Pro9Leu (c.26C>T)?

AlphaMissense predicts likely pathogenic (score 0.9432) — an in-silico prediction, not a clinical call.

FERMT2 p.Pro9Leu

c.26C>T · rs1014128205 · VCV3094466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9432 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9432	likely pathogenic
REVEL	0.338	indeterminate
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 3.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 92 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	31.0	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 0.00667% Admixed American · 4/60,000 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000743% 12/1,614,048 alleles · very rare exomes 9/1,461,828 · genomes 3/152,220 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,000
Remaining individualsnot grpmax-eligible	0.0032%	31,245
African / African-American	0.00133%	74,944
European (non-Finnish)	0.000424%	236,006

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: FERMT2
Protein: p.Pro9Leu
Coding: c.26C>T
MANE Select: NM_006832
dbSNP: rs1014128205
Type: single nucleotide variant
Location: chr14:52950543 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.79 · 6 PDB
Residue 9: a turn

Full FERMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FERMT2 p.Pro9Ser Uncertain significance ★ ⚠ same residue
FERMT2 c.1603-562A>G Uncertain significance ★ same type
FERMT2 c.1603-565G>C Uncertain significance ★ same type
FERMT2 c.1603-566G>C Uncertain significance ★ same type
FERMT2 p.Ala122Gly Uncertain significance ★ same type
FERMT2 p.Ala298Gly Uncertain significance ★ ⚠ same type
FERMT2 p.Ala481Val Uncertain significance ★ ⚠ same type
FERMT2 p.Ala537Val Uncertain significance ★ ⚠ 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/fermt2-p-pro9leu (accessed [today's date]).

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