Is FERMT3 p.Asp491Ala (c.1472A>C) pathogenic?

FERMT3 p.Asp491Ala (c.1472A>C) is classified Uncertain significance in FERMT3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0845); Ultra-rare (popmax 0.0103%, nfe); Associated with leukocyte adhesion deficiency 3.

What condition is associated with FERMT3 p.Asp491Ala (c.1472A>C)?

FERMT3 p.Asp491Ala (c.1472A>C) is associated with leukocyte adhesion deficiency 3 (ClinVar).

How common is FERMT3 p.Asp491Ala (c.1472A>C) in the general population?

FERMT3 p.Asp491Ala (c.1472A>C) is ultra-rare (popmax 0.0103%, nfe) (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.Asp491Ala (c.1472A>C)?

AlphaMissense predicts likely benign (score 0.0845) — an in-silico prediction, not a clinical call.

FERMT3 p.Asp491Ala

c.1472A>C · rs142686129 · VCV645185

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0845 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0103%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukocyte adhesion deficiency 3

Computational evidence

Protein change
AlphaMissense	0.0845	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -4.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.92, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 16 kb · p 2.9e-07 · regional, not allelic
Overall
CADD	22.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 D495A vs ClinVar D491A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0103% European (non-Finnish) · 122/1,178,818 alleles

Filtering AF 0.00885% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00829%

Overall 0.00776% 125/1,610,306 alleles · ultra-rare exomes 119/1,458,100 · genomes 6/152,206 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0103%	9,662
Remaining individualsnot grpmax-eligible	0.00481%	20,776

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.Asp491Ala
Coding: c.1472A>C
MANE Select: NM_031471
dbSNP: rs142686129
Type: single nucleotide variant
Location: chr11:64220596 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.17 (gnomAD)
Structure: AlphaFold pLDDT 83.80 · 6 PDB
Residue 495 UniProt numbering: the ferm domain

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.Asp491His 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
FERMT3 p.Arg129His 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-asp491ala (accessed [today's date]).

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