Is FOXN1 p.Pro558Ser (c.1672C>T) pathogenic?

FOXN1 p.Pro558Ser (c.1672C>T) is classified Uncertain significance in FOXN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-30). AlphaMissense: likely benign (0.3128); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with FOXN1 p.Pro558Ser (c.1672C>T)?

FOXN1 p.Pro558Ser (c.1672C>T) is associated with Inborn genetic diseases, T-cell immunodeficiency, congenital alopecia, and nail dystrophy (ClinVar).

How common is FOXN1 p.Pro558Ser (c.1672C>T) in the general population?

FOXN1 p.Pro558Ser (c.1672C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FOXN1 p.Pro558Ser (c.1672C>T)?

AlphaMissense predicts likely benign (score 0.3128) — an in-silico prediction, not a clinical call.

FOXN1 p.Pro558Ser

c.1672C>T · VCV4620266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3128 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3128	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -5.89	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP -0.92, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,942 bp · p 0.25 · regional, not allelic
Overall
CADD	23.3	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FOXN1
Protein: p.Pro558Ser
Coding: c.1672C>T
MANE Select: NM_001369369
Type: single nucleotide variant
Location: chr17:28537161 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.44 · 2 PDB
Residue 558: a UniProt-annotated variant site (in tidand and tlind); a UniProt-annotated variant site (in tlind)

Full FOXN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Similar variants

FOXN1 p.Pro558= Likely benign ★ same residue
FOXN1 p.Arg114Ter Pathogenic ★★★ same condition
FOXN1 p.Arg255Ter Pathogenic ★★★ same condition
FOXN1 p.Arg320Trp Pathogenic ★★★ same condition
FOXN1 p.Cys82Ter Pathogenic ★★★ same condition
FOXN1 p.Gln474Ter Pathogenic ★★★ same condition
FOXN1 p.His321Arg Likely pathogenic ★★★ same condition
FOXN1 p.Leu325Pro Likely pathogenic ★★★ 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/foxn1-p-pro558ser (accessed [today's date]).

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