Is FERMT2 p.Arg595Leu (c.1784G>T) pathogenic?

FERMT2 p.Arg595Leu (c.1784G>T) is classified Uncertain significance in FERMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-05). AlphaMissense: likely pathogenic (0.6122); Very rare (popmax 0.000763%, nfe).

How common is FERMT2 p.Arg595Leu (c.1784G>T) in the general population?

FERMT2 p.Arg595Leu (c.1784G>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about FERMT2 p.Arg595Leu (c.1784G>T)?

AlphaMissense predicts likely pathogenic (score 0.6122) — an in-silico prediction, not a clinical call.

FERMT2 p.Arg595Leu

c.1784G>T · rs377196292 · VCV2602776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6122 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6122	likely pathogenic
REVEL	0.694	pathogenic-leaning
SaProt	LLR -12.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	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 0.000763% European (non-Finnish) · 9/1,179,212 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,612,586 alleles · very rare exomes 9/1,460,384 · genomes 0/152,202 · 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: FERMT2
Protein: p.Arg595Leu
Coding: c.1784G>T
MANE Select: NM_006832
dbSNP: rs377196292
Type: single nucleotide variant
Location: chr14:52859658 (GRCh38)
Gene constraint: LOEUF 0.304 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.79 · 6 PDB
Residue 595: the ferm domain; a β-strand

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

Similar variants

FERMT2 p.Arg595Gln 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-arg595leu (accessed [today's date]).

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