Is HR p.Pro480= (c.1440G>A) pathogenic?

HR p.Pro480= (c.1440G>A) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0332%, mid); Associated with alopecia universalis congenita.

What condition is associated with HR p.Pro480= (c.1440G>A)?

HR p.Pro480= (c.1440G>A) is associated with alopecia universalis congenita, atrichia with papular lesions (ClinVar).

How common is HR p.Pro480= (c.1440G>A) in the general population?

HR p.Pro480= (c.1440G>A) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

How is Alopecia universalis inherited?

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

HR p.Pro480=

c.1440G>A · rs761705307 · VCV908154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Conditions

alopecia universalis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.1	GERP -3.3
Overall
CADD	0.426	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,032 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00384% 62/1,613,806 alleles · ultra-rare exomes 54/1,461,580 · genomes 8/152,226 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,016
Admixed American	0.0167%	5,999
African / African-American	0.016%	6,244
South Asian	0.011%	9,103
Remaining individualsnot grpmax-eligible	0.0048%	20,821
East Asian	0.00223%	44,884
European (non-Finnish)	0.00195%	51,304
Finnishnot grpmax-eligible	0.00156%	63,956

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: HR
Protein: p.Pro480=
Coding: c.1440G>A
MANE Select: NM_005144
dbSNP: rs761705307
Type: single nucleotide variant
Location: chr8:22125698 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 480: the 'disordered' region

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

Disease context

alopecia universalis congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atrichia with papular lesions

For Alopecia universalis (Orphanet):

Inheritance: Autosomal recessive, Multigenic/multifactorial
Onset: All ages
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

HR p.Pro480Leu Uncertain significance ★★ ⚠ same residue
HR p.Arg940Ter Pathogenic ★★ same condition
HR c.*180G>A Uncertain significance ★★ same condition
HR c.*295G>A Uncertain significance ★★ same condition
HR p.Arg1099Leu Uncertain significance ★★ ⚠ same condition
HR p.Arg518Trp Uncertain significance ★★ ⚠ same condition
HR p.Arg856Gly Uncertain significance ★★ ⚠ same condition
HR p.Arg998Gln 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/hr-p-pro480 (accessed [today's date]).

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