Is HR p.Trp186Cys (c.558G>C) pathogenic?

HR p.Trp186Cys (c.558G>C) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-09). AlphaMissense: likely pathogenic (0.5868); Very rare (popmax 0.00501%, nfe).

How common is HR p.Trp186Cys (c.558G>C) in the general population?

HR p.Trp186Cys (c.558G>C) is very rare (popmax 0.00501%, nfe) (gnomAD).

What do computational predictors say about HR p.Trp186Cys (c.558G>C)?

AlphaMissense predicts likely pathogenic (score 0.5868) — an in-silico prediction, not a clinical call.

HR p.Trp186Cys

c.558G>C · rs746154352 · VCV3008023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.5868	likely pathogenic
REVEL	0.421	indeterminate
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.58, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	23.5	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 0.00501% European (non-Finnish) · 59/1,177,624 alleles

Filtering AF 0.00394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00361%

Overall 0.00367% 59/1,606,820 alleles · very rare exomes 57/1,454,618 · genomes 2/152,202 · joint denominator

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.Trp186Cys
Coding: c.558G>C
MANE Select: NM_005144
dbSNP: rs746154352
Type: single nucleotide variant
Location: chr8:22128613 (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

Similar variants

HR p.Trp186Ter Likely pathogenic ★ same residue
HR c.-320T>A Pathogenic/Likely pathogenic ★★ same type
HR p.Arg819Ter Pathogenic/Likely pathogenic ★★ same type
HR p.Arg940Ter Pathogenic ★★ same type
HR p.Cys622Gly Pathogenic/Likely pathogenic ★★ same type
HR c.*180G>A Uncertain significance ★★ same type
HR c.*295G>A Uncertain significance ★★ same type
HR p.Ala1188Asp Uncertain significance ★★ ⚠ same type

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-trp186cys (accessed [today's date]).

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