Is FERMT2 p.Pro417Arg (c.1250C>G) pathogenic?

FERMT2 p.Pro417Arg (c.1250C>G) is classified Uncertain significance in FERMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.8523); Ultra-rare (popmax 0.036%, afr).

How common is FERMT2 p.Pro417Arg (c.1250C>G) in the general population?

FERMT2 p.Pro417Arg (c.1250C>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about FERMT2 p.Pro417Arg (c.1250C>G)?

AlphaMissense predicts likely pathogenic (score 0.8523) — an in-silico prediction, not a clinical call.

FERMT2 p.Pro417Arg

c.1250C>G · VCV4024480

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8523	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -17.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 92 kb · p 7.5e-09 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.036% African / African-American · 27/75,028 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.00223% 36/1,613,862 alleles · ultra-rare exomes 16/1,461,616 · genomes 20/152,246 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,779
Admixed American	0.0133%	7,500
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Pro417Arg
Coding: c.1250C>G
MANE Select: NM_006832
Type: single nucleotide variant
Location: chr14:52872822 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.79 · 6 PDB
Residue 417: the ferm domain; the ph domain

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

Similar variants

FERMT2 p.Pro417Gln 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-pro417arg (accessed [today's date]).

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