Is HR p.Pro40= (c.120G>A) pathogenic?

HR p.Pro40= (c.120G>A) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0375%, amr); Associated with atrichia with papular lesions.

What condition is associated with HR p.Pro40= (c.120G>A)?

HR p.Pro40= (c.120G>A) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Pro40= (c.120G>A) in the general population?

HR p.Pro40= (c.120G>A) is ultra-rare (popmax 0.0375%, amr) (gnomAD).

How is Atrichia with papular lesions inherited?

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

HR p.Pro40=

c.120G>A · rs757776752 · VCV362531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0375%, amr)

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 -6.3	GERP -2.8
Overall
CADD	1.348	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0375% Admixed American · 22/58,694 alleles

Filtering AF 0.0253% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.00213% 34/1,599,246 alleles · ultra-rare exomes 28/1,447,042 · genomes 6/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0375%	2,668
Remaining individualsnot grpmax-eligible	0.00486%	20,593
African / African-American	0.00268%	37,250
South Asian	0.00225%	44,530
European (non-Finnish)	0.000427%	234,462

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.Pro40=
Coding: c.120G>A
MANE Select: NM_005144
dbSNP: rs757776752
Type: single nucleotide variant
Location: chr8:22129051 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 40: 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.Pro40Gln Uncertain significance ★★ ⚠ same residue
HR p.Pro40Ser Uncertain significance ★ ⚠ same residue
HR p.Pro40Leu Benign 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

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-pro40 (accessed [today's date]).

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