Is HR p.Ser789= (c.2367T>C) pathogenic?

HR p.Ser789= (c.2367T>C) is classified Benign in HR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-02). Common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with alopecia universalis congenita.

What condition is associated with HR p.Ser789= (c.2367T>C)?

HR p.Ser789= (c.2367T>C) is associated with alopecia universalis congenita, atrichia with papular lesions (ClinVar).

How is Alopecia universalis inherited?

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

HR p.Ser789=

Q: How common is HR p.Ser789= (c.2367T>C) in the general population?

HR p.Ser789= (c.2367T>C) is common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2367T>C · rs58080661 · VCV362497

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 32.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

alopecia universalis congenita

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.41	donor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2	GERP -3.1
Overall
CADD	1.356	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 32.9% African / African-American · 24,648/74,994 alleles

Filtering AF 32.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.4%

Overall 3.49% 56,353/1,613,446 alleles · common exomes 39,867/1,461,252 · genomes 16,486/152,194 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	32.9%	3
Ashkenazi Jewishnot grpmax-eligible	7.93%	13
Middle Eastern	7.19%	14
Remaining individualsnot grpmax-eligible	5%	20
Admixed American	4.21%	24
South Asian	3.24%	31
Finnishnot grpmax-eligible	2.17%	46
European (non-Finnish)	1.56%	64
East Asian	1.22%	82
Amishnot grpmax-eligible	0.219%	456

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.Ser789=
Coding: c.2367T>C
MANE Select: NM_005144
dbSNP: rs58080661
Type: single nucleotide variant
Location: chr8:22121065 (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.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-ser789 (accessed [today's date]).

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