Is FERMT3 p.Arg640Trp (c.1918C>T) pathogenic?

FERMT3 p.Arg640Trp (c.1918C>T) is classified Uncertain significance in FERMT3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-14). AlphaMissense: likely pathogenic (0.7185); Ultra-rare (popmax 0.0164%, mid); Associated with leukocyte adhesion deficiency 3.

What condition is associated with FERMT3 p.Arg640Trp (c.1918C>T)?

FERMT3 p.Arg640Trp (c.1918C>T) is associated with leukocyte adhesion deficiency 3 (ClinVar).

How common is FERMT3 p.Arg640Trp (c.1918C>T) in the general population?

FERMT3 p.Arg640Trp (c.1918C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Leukocyte adhesion deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FERMT3 p.Arg640Trp (c.1918C>T)?

AlphaMissense predicts likely pathogenic (score 0.7185) — an in-silico prediction, not a clinical call.

FERMT3 p.Arg640Trp

c.1918C>T · rs886043481 · VCV286800

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7185 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

leukocyte adhesion deficiency 3

Computational evidence

Protein change
AlphaMissense	0.7185	likely pathogenic
REVEL	0.603	indeterminate
SaProt	LLR -13.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 0.85, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.9e-07 · regional, not allelic
Overall
CADD	26.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R644W vs ClinVar R640W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00093% 15/1,613,460 alleles · ultra-rare exomes 14/1,461,242 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00445%	22,449
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00158%	63,404
European (non-Finnish)	0.000763%	131,115

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: FERMT3
Protein: p.Arg640Trp
Coding: c.1918C>T
MANE Select: NM_031471
dbSNP: rs886043481
Type: single nucleotide variant
Location: chr11:64223418 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.80 · 6 PDB
Residue 644 UniProt numbering: a turn

Full FERMT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukocyte adhesion deficiency 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Leukocyte adhesion deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

FERMT3 p.Arg640= Likely benign ★ same residue
FERMT3 p.Arg640Gly Uncertain significance ★ same residue
FERMT3 p.Arg573Ter Pathogenic/Likely pathogenic ★★ same condition
FERMT3 p.Ala109Thr Uncertain significance ★★ ⚠ same condition
FERMT3 p.Ala338Val Uncertain significance ★★ ⚠ same condition
FERMT3 p.Ala570Thr Uncertain significance ★★ ⚠ same condition
FERMT3 p.Arg103Gln Uncertain significance ★★ ⚠ same condition
FERMT3 p.Arg111His 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/fermt3-p-arg640trp (accessed [today's date]).

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