Is HR p.Pro46Ala (c.136C>G) pathogenic?

HR p.Pro46Ala (c.136C>G) is classified Uncertain significance in HR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-15). AlphaMissense: likely benign (0.0652); Very rare (popmax 0.00506%, amr); Associated with atrichia with papular lesions.

What condition is associated with HR p.Pro46Ala (c.136C>G)?

HR p.Pro46Ala (c.136C>G) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Pro46Ala (c.136C>G) in the general population?

HR p.Pro46Ala (c.136C>G) is very rare (popmax 0.00506%, amr) (gnomAD).

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.Pro46Ala (c.136C>G)?

AlphaMissense predicts likely benign (score 0.0652) — an in-silico prediction, not a clinical call.

HR p.Pro46Ala

c.136C>G · rs760827763 · VCV911061

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00506%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrichia with papular lesions

Computational evidence

Protein change
AlphaMissense	0.0652	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.28, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00506% Admixed American · 3/59,268 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000672%

Overall 0.000685% 11/1,605,560 alleles · very rare exomes 11/1,453,234 · genomes 0/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00506%	19,756
European (non-Finnish)	0.000681%	146,945

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.Pro46Ala
Coding: c.136C>G
MANE Select: NM_005144
dbSNP: rs760827763
Type: single nucleotide variant
Location: chr8:22129035 (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.Pro46Leu 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-pro46ala (accessed [today's date]).

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