Is FERMT1 p.Ala533= (c.1599C>T) pathogenic?

FERMT1 p.Ala533= (c.1599C>T) is classified Conflicting classifications of pathogenicity in FERMT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-27). Ultra-rare (popmax 0.087%, eas); Associated with Kindler syndrome.

What condition is associated with FERMT1 p.Ala533= (c.1599C>T)?

FERMT1 p.Ala533= (c.1599C>T) is associated with Kindler syndrome (ClinVar).

How common is FERMT1 p.Ala533= (c.1599C>T) in the general population?

FERMT1 p.Ala533= (c.1599C>T) is ultra-rare (popmax 0.087%, eas) (gnomAD).

How is Kindler epidermolysis bullosa inherited?

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

FERMT1 p.Ala533=

c.1599C>T · rs774007627 · VCV896232

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.087%, eas)

Conditions

Kindler syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.5	GERP -4.3
Overall
CADD	8.893	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.087% East Asian · 39/44,816 alleles

Filtering AF 0.0654% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00701% 113/1,610,924 alleles · ultra-rare exomes 104/1,458,728 · genomes 9/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.087%	1,149
African / African-American	0.012%	8,318
European (non-Finnish)	0.00526%	19,011
Admixed American	0.00168%	59,464
Remaining individualsnot grpmax-eligible	0.0016%	62,368
South Asian	0.0011%	90,524

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: FERMT1
Protein: p.Ala533=
Coding: c.1599C>T
MANE Select: NM_017671
dbSNP: rs774007627
Type: single nucleotide variant
Location: chr20:6084159 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14
Residue 533: the ferm domain

Full FERMT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Kindler syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Kindler epidermolysis bullosa (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

FERMT1 p.Ala533Val Uncertain significance ★ ⚠ same residue
FERMT1 c.1371+4A>G Pathogenic ★★ same condition
FERMT1 p.Arg110Ter Pathogenic ★★ same condition
FERMT1 p.Arg271Ter Pathogenic ★★ same condition
FERMT1 p.Arg288Ter Pathogenic ★★ same condition
FERMT1 p.Glu304Ter Pathogenic ★★ same condition
FERMT1 c.*1004G>A Uncertain significance ★★ same condition
FERMT1 c.*1076C>T 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/fermt1-p-ala533 (accessed [today's date]).

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