Is HR p.Pro63Arg (c.188C>G) pathogenic?

HR p.Pro63Arg (c.188C>G) is classified Benign in HR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-08). AlphaMissense: likely benign (0.0941); Common (popmax 10%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atrichia with papular lesions.

What condition is associated with HR p.Pro63Arg (c.188C>G)?

HR p.Pro63Arg (c.188C>G) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How is Atrichia with papular lesions inherited?

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

What do computational predictors say about HR p.Pro63Arg (c.188C>G)?

AlphaMissense predicts likely benign (score 0.0941) — an in-silico prediction, not a clinical call.

HR p.Pro63Arg

Q: How common is HR p.Pro63Arg (c.188C>G) in the general population?

HR p.Pro63Arg (c.188C>G) is common (popmax 10%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.188C>G · rs73549525 · VCV362529

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0941 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrichia with papular lesions

Computational evidence

Protein change
AlphaMissense	0.0941	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -7.13	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 6.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	22.2	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 10% African / African-American · 7,528/75,040 alleles

Filtering AF 9.84% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.76%

Overall 0.552% 8,908/1,613,254 alleles · common exomes 4,601/1,460,940 · genomes 4,307/152,314 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10%	10
Remaining individualsnot grpmax-eligible	0.789%	127
Ashkenazi Jewishnot grpmax-eligible	0.619%	162
Admixed American	0.603%	166
Middle Eastern	0.577%	173
South Asian	0.0296%	3,373
European (non-Finnish)	0.0237%	4,214

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.Pro63Arg
Coding: c.188C>G
MANE Select: NM_005144
dbSNP: rs73549525
Type: single nucleotide variant
Location: chr8:22128983 (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

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-pro63arg (accessed [today's date]).

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