Is HR p.Phe435= (c.1305T>C) pathogenic?

HR p.Phe435= (c.1305T>C) is classified Benign/Likely benign in HR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-04). Common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with atrichia with papular lesions.

What condition is associated with HR p.Phe435= (c.1305T>C)?

HR p.Phe435= (c.1305T>C) is associated with atrichia with papular lesions, alopecia universalis congenita (ClinVar).

How is Atrichia with papular lesions inherited?

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

HR p.Phe435=

Q: How common is HR p.Phe435= (c.1305T>C) in the general population?

HR p.Phe435= (c.1305T>C) is common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1305T>C · rs12675745 · VCV362521

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Common

common (popmax 70.3%, afr) — too common for a highly-penetrant pathogenic allele

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 5.1	GERP -0.63, phastCons 1
Overall
CADD	8.994	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 70.3% African / African-American · 52,720/74,974 alleles

Filtering AF 69.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.6%

Overall 61.8% 995,730/1,611,568 alleles · common exomes 899,566/1,459,412 · genomes 96,164/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	70.3%	1
Ashkenazi Jewishnot grpmax-eligible	69.8%	1
Middle Eastern	67.2%	1
South Asian	66.2%	2
Finnishnot grpmax-eligible	63.1%	2
Amishnot grpmax-eligible	62.7%	2
Remaining individualsnot grpmax-eligible	62%	2
European (non-Finnish)	61.9%	2
Admixed American	51.4%	2
East Asian	42.1%	2

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.Phe435=
Coding: c.1305T>C
MANE Select: NM_005144
dbSNP: rs12675745
Type: single nucleotide variant
Location: chr8:22127137 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 435: 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-phe435 (accessed [today's date]).

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