Is HR p.Pro69Ser (c.205C>T) pathogenic?

HR p.Pro69Ser (c.205C>T) is classified Benign/Likely benign in HR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0823); Rare (popmax 0.487%, nfe); Associated with alopecia universalis congenita.

What condition is associated with HR p.Pro69Ser (c.205C>T)?

HR p.Pro69Ser (c.205C>T) is associated with alopecia universalis congenita, atrichia with papular lesions (ClinVar).

How common is HR p.Pro69Ser (c.205C>T) in the general population?

HR p.Pro69Ser (c.205C>T) is rare (popmax 0.487%, nfe) (gnomAD).

How is Alopecia universalis inherited?

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

What do computational predictors say about HR p.Pro69Ser (c.205C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

HR p.Pro69Ser

c.205C>T · rs78621054 · VCV770746

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.487%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alopecia universalis congenita

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP 0.28, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	12.14	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.487% European (non-Finnish) · 5,749/1,179,990 alleles

Filtering AF 0.477% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.472%

Overall 0.401% 6,469/1,613,386 alleles · rare exomes 5,973/1,461,028 · genomes 496/152,358 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.487%	205
Ashkenazi Jewishnot grpmax-eligible	0.487%	205
Remaining individualsnot grpmax-eligible	0.36%	278
Admixed American	0.187%	536
Middle Eastern	0.132%	758
South Asian	0.124%	806
African / African-American	0.0946%	1,057
Finnishnot grpmax-eligible	0.0743%	1,346

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.Pro69Ser
Coding: c.205C>T
MANE Select: NM_005144
dbSNP: rs78621054
Type: single nucleotide variant
Location: chr8:22128966 (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-pro69ser (accessed [today's date]).

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