Is HR p.Pro426Ser (c.1276C>T) pathogenic?

HR p.Pro426Ser (c.1276C>T) is classified Uncertain significance in HR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.0866%, amr); Associated with atrichia with papular lesions.

What condition is associated with HR p.Pro426Ser (c.1276C>T)?

HR p.Pro426Ser (c.1276C>T) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How common is HR p.Pro426Ser (c.1276C>T) in the general population?

HR p.Pro426Ser (c.1276C>T) is ultra-rare (popmax 0.0866%, 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.Pro426Ser (c.1276C>T)?

AlphaMissense predicts likely benign (score 0.0978) — an in-silico prediction, not a clinical call.

HR p.Pro426Ser

c.1276C>T · rs151036296 · VCV362522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0978 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrichia with papular lesions

Computational evidence

Protein change
AlphaMissense	0.0978	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -7.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	22.4	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 0.0866% Admixed American · 52/60,024 alleles

Filtering AF 0.0678% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0611%

Overall 0.0505% 815/1,612,866 alleles · ultra-rare exomes 734/1,460,500 · genomes 81/152,366 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0866%	1,154
Remaining individualsnot grpmax-eligible	0.0752%	1,330
European (non-Finnish)	0.0596%	1,678
Middle Eastern	0.033%	3,031
African / African-American	0.0133%	7,507
South Asian	0.0011%	91,064

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.Pro426Ser
Coding: c.1276C>T
MANE Select: NM_005144
dbSNP: rs151036296
Type: single nucleotide variant
Location: chr8:22127166 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 426: 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-pro426ser (accessed [today's date]).

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