Is HR p.Ser453= (c.1359G>A) pathogenic?

HR p.Ser453= (c.1359G>A) is classified Benign in HR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-21). Low-frequency (popmax 1.25%, nfe); Associated with atrichia with papular lesions.

What condition is associated with HR p.Ser453= (c.1359G>A)?

HR p.Ser453= (c.1359G>A) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Ser453= (c.1359G>A) in the general population?

HR p.Ser453= (c.1359G>A) is low-frequency (popmax 1.25%, nfe) (gnomAD).

How is Atrichia with papular lesions inherited?

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

HR p.Ser453=

c.1359G>A · rs78489044 · VCV910113

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.25%, nfe)

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 -5.3	GERP -3.5
Overall
CADD	0.089	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.25% European (non-Finnish) · 14,785/1,179,446 alleles

Filtering AF 1.24% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.23%

Overall 1.09% 17,617/1,611,904 alleles · low-frequency exomes 16,256/1,459,676 · genomes 1,361/152,228 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.26%	44
European (non-Finnish)grpmax	1.25%	80
Ashkenazi Jewishnot grpmax-eligible	1.23%	82
Remaining individualsnot grpmax-eligible	0.919%	109
Admixed American	0.5%	200
Amishnot grpmax-eligible	0.33%	303
Middle Eastern	0.248%	403
African / African-American	0.168%	595
South Asian	0.0374%	2,674
East Asian	0.00446%	22,432

Finnish 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.Ser453=
Coding: c.1359G>A
MANE Select: NM_005144
dbSNP: rs78489044
Type: single nucleotide variant
Location: chr8:22127083 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 453: the 'disordered' region

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-ser453 (accessed [today's date]).

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