Is FERMT1 p.Ala558= (c.1674G>A) pathogenic?

FERMT1 p.Ala558= (c.1674G>A) is classified Benign in FERMT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). Common (popmax 24.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Kindler syndrome.

What condition is associated with FERMT1 p.Ala558= (c.1674G>A)?

FERMT1 p.Ala558= (c.1674G>A) is associated with Kindler syndrome (ClinVar).

How is Kindler epidermolysis bullosa inherited?

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

FERMT1 p.Ala558=

Q: How common is FERMT1 p.Ala558= (c.1674G>A) in the general population?

FERMT1 p.Ala558= (c.1674G>A) is common (popmax 24.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1674G>A · rs2232079 · VCV339209

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 24.2%, afr) — too common for a highly-penetrant pathogenic allele

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 -11	GERP -4.3
Overall
CADD	3.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 24.2% African / African-American · 18,173/74,986 alleles

Filtering AF 23.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.8%

Overall 11.2% 181,240/1,613,008 alleles · common exomes 160,175/1,460,788 · genomes 21,065/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	24.2%	4
Remaining individualsnot grpmax-eligible	11.5%	9
European (non-Finnish)	11.4%	9
Middle Eastern	9.07%	11
Finnishnot grpmax-eligible	8.79%	11
Admixed American	8.23%	12
Ashkenazi Jewishnot grpmax-eligible	7.7%	13
Amishnot grpmax-eligible	6.8%	15
East Asian	6.28%	16
South Asian	6.06%	17

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.Ala558=
Coding: c.1674G>A
MANE Select: NM_017671
dbSNP: rs2232079
Type: single nucleotide variant
Location: chr20:6084084 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14
Residue 558: 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.Ala558Val 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-ala558 (accessed [today's date]).

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