Is FOXN1 p.Ala599Pro (c.1795G>C) pathogenic?

FOXN1 p.Ala599Pro (c.1795G>C) is classified Benign in FOXN1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0579); Common (popmax 58.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy.

What condition is associated with FOXN1 p.Ala599Pro (c.1795G>C)?

FOXN1 p.Ala599Pro (c.1795G>C) is associated with T-cell immunodeficiency, congenital alopecia, and nail dystrophy (ClinVar).

What do computational predictors say about FOXN1 p.Ala599Pro (c.1795G>C)?

AlphaMissense predicts likely benign (score 0.0579) — an in-silico prediction, not a clinical call.

FOXN1 p.Ala599Pro

Q: How common is FOXN1 p.Ala599Pro (c.1795G>C) in the general population?

FOXN1 p.Ala599Pro (c.1795G>C) is common (popmax 58.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1795G>C · rs532648 · VCV322436

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0579 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 58.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.0579	likely benign
REVEL	0.202	benign-leaning
SaProt	LLR -6.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP -3.6
Regional constraint	o/e 0.94	unconstrained · MANE · 2,942 bp · p 0.25 · regional, not allelic
Overall
CADD	5.257	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 58.4% African / African-American · 43,777/74,902 alleles

Filtering AF 58% ClinGen BA1/BS1 input FAF95, joint · FAF99 57.8%

Overall 31% 499,800/1,613,382 alleles · common exomes 441,861/1,461,400 · genomes 57,939/151,982 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	58.4%	2
Amishnot grpmax-eligible	37.6%	3
Middle Eastern	37.3%	3
Admixed American	36.6%	3
Finnishnot grpmax-eligible	32.3%	3
Remaining individualsnot grpmax-eligible	31.5%	3
South Asian	30.5%	3
European (non-Finnish)	29.2%	3
Ashkenazi Jewishnot grpmax-eligible	28%	4
East Asian	23.4%	4

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.Ala599Pro
Coding: c.1795G>C
MANE Select: NM_001369369
dbSNP: rs532648
Type: single nucleotide variant
Location: chr17:28537284 (GRCh38)
Gene constraint: LOEUF 0.442 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.44 · 2 PDB
Residue 599: a UniProt-annotated variant site (in tidand and tlind); a UniProt-annotated variant site (in tlind); a UniProt-annotated variant site (in)

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.Ala599= Likely benign ★ same residue
FOXN1 p.Ala599His Uncertain significance ★ 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

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-ala599pro (accessed [today's date]).

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