Is FERMT2 p.Arg595Gln (c.1784G>A) pathogenic?

FERMT2 p.Arg595Gln (c.1784G>A) is classified Uncertain significance in FERMT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-11). AlphaMissense: likely benign (0.2762); Ultra-rare (popmax 0.0281%, afr).

How common is FERMT2 p.Arg595Gln (c.1784G>A) in the general population?

FERMT2 p.Arg595Gln (c.1784G>A) is ultra-rare (popmax 0.0281%, afr) (gnomAD).

What do computational predictors say about FERMT2 p.Arg595Gln (c.1784G>A)?

AlphaMissense predicts likely benign (score 0.2762) — an in-silico prediction, not a clinical call.

FERMT2 p.Arg595Gln

c.1784G>A · VCV3849954

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2762 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0281%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2762	likely benign
REVEL	0.749	pathogenic-leaning
SaProt	LLR -8.44	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
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	29.5	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 0.0281% African / African-American · 21/74,834 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00583% 94/1,612,466 alleles · ultra-rare exomes 85/1,460,382 · genomes 9/152,084 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0281%	3,564
Admixed American	0.00668%	14,975
European (non-Finnish)	0.0056%	17,867
Remaining individualsnot grpmax-eligible	0.00481%	20,807

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.Arg595Gln
Coding: c.1784G>A
MANE Select: NM_006832
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.Arg595Leu 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-arg595gln (accessed [today's date]).

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