Is FERMT1 p.Ser400Pro (c.1198T>C) pathogenic?

FERMT1 p.Ser400Pro (c.1198T>C) is classified Pathogenic in FERMT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2010-02-08). AlphaMissense: likely pathogenic (0.9466); Very rare (popmax 0.000255%, nfe); Associated with Kindler syndrome.

What condition is associated with FERMT1 p.Ser400Pro (c.1198T>C)?

FERMT1 p.Ser400Pro (c.1198T>C) is associated with Kindler syndrome (ClinVar).

How common is FERMT1 p.Ser400Pro (c.1198T>C) in the general population?

FERMT1 p.Ser400Pro (c.1198T>C) is very rare (popmax 0.000255%, nfe) (gnomAD).

How is Kindler epidermolysis bullosa inherited?

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

What do computational predictors say about FERMT1 p.Ser400Pro (c.1198T>C)?

AlphaMissense predicts likely pathogenic (score 0.9466) — an in-silico prediction, not a clinical call.

FERMT1 p.Ser400Pro

c.1198T>C · rs869312718 · VCV224165

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9466 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kindler syndrome

Computational evidence

Protein change
AlphaMissense	0.9466	likely pathogenic ✓ concordant with ClinVar · top 7% in FERMT1
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -13.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 42 kb · p 3.8e-05 · regional, not allelic
Overall
CADD	25.4	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 0.000255% European (non-Finnish) · 3/1,178,158 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,611,650 alleles · very rare exomes 3/1,459,592 · genomes 0/152,058 · joint denominator

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.Ser400Pro
Coding: c.1198T>C
MANE Select: NM_017671
dbSNP: rs869312718
Type: single nucleotide variant
Location: chr20:6089031 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14
Residue 400: the ferm domain; a UniProt-annotated variant site (in kndlrs); the ph 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 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
FERMT1 c.*2124C>A 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-ser400pro (accessed [today's date]).

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