Is HR p.Leu554= (c.1662C>T) pathogenic?

HR p.Leu554= (c.1662C>T) is classified Conflicting classifications of pathogenicity in HR (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-31). Ultra-rare (popmax 0.0823%, mid); Associated with atrichia with papular lesions.

What condition is associated with HR p.Leu554= (c.1662C>T)?

HR p.Leu554= (c.1662C>T) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Leu554= (c.1662C>T) in the general population?

HR p.Leu554= (c.1662C>T) is ultra-rare (popmax 0.0823%, mid) (gnomAD).

How is Atrichia with papular lesions inherited?

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

HR p.Leu554=

c.1662C>T · rs369191252 · VCV912098

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0823%, mid)

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 -9	GERP -2.8
Overall
CADD	0.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0823% Middle Eastern · 5/6,078 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00366% 59/1,611,738 alleles · ultra-rare exomes 50/1,459,466 · genomes 9/152,272 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0823%	1,216
Remaining individualsnot grpmax-eligible	0.0144%	6,934
European (non-Finnish)	0.00339%	29,488
Admixed American	0.00334%	29,929
South Asian	0.00221%	45,291
African / African-American	0.00133%	74,942

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.Leu554=
Coding: c.1662C>T
MANE Select: NM_005144
dbSNP: rs369191252
Type: single nucleotide variant
Location: chr8:22125399 (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-leu554 (accessed [today's date]).

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