Is HR p.Pro842= (c.2526A>C) pathogenic?

HR p.Pro842= (c.2526A>C) is classified Benign/Likely benign in HR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). Low-frequency (popmax 1%, mid); Associated with alopecia universalis congenita.

What condition is associated with HR p.Pro842= (c.2526A>C)?

HR p.Pro842= (c.2526A>C) is associated with alopecia universalis congenita, atrichia with papular lesions (ClinVar).

How common is HR p.Pro842= (c.2526A>C) in the general population?

HR p.Pro842= (c.2526A>C) is low-frequency (popmax 1%, 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.Pro842=

c.2526A>C · rs371431900 · VCV362492

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1%, mid)

Conditions

alopecia universalis congenita

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 -12	GERP -3.2
Overall
CADD	0.009	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1% Middle Eastern · 59/5,898 alleles

Filtering AF 0.867% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.846%

Overall 0.176% 2,726/1,544,550 alleles · low-frequency exomes 2,393/1,392,314 · genomes 333/152,236 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.64%	38
Middle Easterngrpmax	1%	100
South Asian	0.921%	109
Remaining individualsnot grpmax-eligible	0.354%	283
African / African-American	0.326%	307
Admixed American	0.0963%	1,038
Finnishnot grpmax-eligible	0.0567%	1,764
European (non-Finnish)	0.0534%	1,873
East Asian	0.0049%	20,420

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro842=
Coding: c.2526A>C
MANE Select: NM_005144
dbSNP: rs371431900
Type: single nucleotide variant
Location: chr8:22120800 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65

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.Pro842Ala Uncertain significance ★ ⚠ same residue
HR p.Pro842Gln Uncertain significance ★ ⚠ same residue
HR p.Pro842Leu 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

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-pro842 (accessed [today's date]).

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