Is HR p.Ala652= (c.1956C>T) pathogenic?

HR p.Ala652= (c.1956C>T) is classified Benign in HR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Low-frequency (popmax 1.57%, eas); Associated with atrichia with papular lesions.

What condition is associated with HR p.Ala652= (c.1956C>T)?

HR p.Ala652= (c.1956C>T) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Ala652= (c.1956C>T) in the general population?

HR p.Ala652= (c.1956C>T) is low-frequency (popmax 1.57%, eas) (gnomAD).

How is Atrichia with papular lesions inherited?

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

HR p.Ala652=

c.1956C>T · rs78939934 · VCV909985

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.57%, eas)

Conditions

atrichia with papular lesions

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.064	GERP -3.4, phastCons 0.006
Overall
CADD	7.608	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.57% East Asian · 649/41,232 alleles

Filtering AF 1.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.43%

Overall 0.27% 4,201/1,555,964 alleles · low-frequency exomes 3,734/1,403,682 · genomes 467/152,282 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.64%	38
East Asiangrpmax	1.57%	64
South Asian	1.14%	88
Middle Eastern	1.04%	96
Remaining individualsnot grpmax-eligible	0.478%	209
African / African-American	0.365%	274
Admixed American	0.106%	944
European (non-Finnish)	0.0982%	1,018
Finnishnot grpmax-eligible	0.057%	1,753

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.Ala652=
Coding: c.1956C>T
MANE Select: NM_005144
dbSNP: rs78939934
Type: single nucleotide variant
Location: chr8:22122839 (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-ala652 (accessed [today's date]).

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