Is HR p.Pro28= (c.84C>T) pathogenic?

HR p.Pro28= (c.84C>T) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Very rare (popmax 0.00834%, nfe); Associated with atrichia with papular lesions.

What condition is associated with HR p.Pro28= (c.84C>T)?

HR p.Pro28= (c.84C>T) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Pro28= (c.84C>T) in the general population?

HR p.Pro28= (c.84C>T) is very rare (popmax 0.00834%, nfe) (gnomAD).

How is Atrichia with papular lesions inherited?

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

HR p.Pro28=

c.84C>T · rs543229110 · VCV912298

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00834%, nfe)

Conditions

atrichia with papular lesions

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 -8.4	GERP -2.8
Overall
CADD	1.196	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% European (non-Finnish) · 97/1,162,752 alleles

Filtering AF 0.00699% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00643%

Overall 0.00705% 111/1,575,272 alleles · very rare exomes 99/1,423,076 · genomes 12/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00834%	11,987
African / African-American	0.00815%	12,264
Remaining individualsnot grpmax-eligible	0.00659%	15,185
South Asian	0.00239%	41,854
Admixed American	0.00184%	54,464
Finnishnot grpmax-eligible	0.00161%	61,960

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.Pro28=
Coding: c.84C>T
MANE Select: NM_005144
dbSNP: rs543229110
Type: single nucleotide variant
Location: chr8:22129087 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 28: the 'disordered' region

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

Disease context

atrichia with papular lesions — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: alopecia universalis congenita

For Atrichia with papular lesions (Orphanet):

Inheritance: Autosomal recessive

Similar variants

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
HR p.Glu985Lys 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-pro28 (accessed [today's date]).

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