Is FOXN1 p.Lys331= (c.993G>A) pathogenic?

FOXN1 p.Lys331= (c.993G>A) is classified Likely benign in FOXN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-28). Very rare (popmax 0.00223%, eas); Associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy.

What condition is associated with FOXN1 p.Lys331= (c.993G>A)?

FOXN1 p.Lys331= (c.993G>A) is associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy (ClinVar).

How common is FOXN1 p.Lys331= (c.993G>A) in the general population?

FOXN1 p.Lys331= (c.993G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

FOXN1 p.Lys331=

Q: How is Severe combined immunodeficiency due to FOXN1 deficiency inherited?

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

c.993G>A · rs933053205 · VCV2784997

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

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 3.1	GERP -2.7, phastCons 1
Overall
CADD	6.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,894 alleles

Overall 0.000186% 3/1,614,064 alleles · very rare exomes 2/1,461,884 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,894
African / African-American	0.00133%	74,926
European (non-Finnish)	8.47e-05%	1,180,034

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: FOXN1
Protein: p.Lys331=
Coding: c.993G>A
MANE Select: NM_001369369
dbSNP: rs933053205
Type: single nucleotide variant
Location: chr17:28534396 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.44 · 2 PDB
Residue 331: a DNA-binding region; a UniProt-annotated variant site (in tidand and tlind); a β-strand

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

Disease context

T-cell immunodeficiency, congenital alopecia, and nail dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe combined immunodeficiency due to FOXN1 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

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
FOXN1 p.Leu456Ter 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-lys331 (accessed [today's date]).

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