Is HR p.Leu830Arg (c.2489T>G) pathogenic?

HR p.Leu830Arg (c.2489T>G) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.1415); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with HR p.Leu830Arg (c.2489T>G)?

HR p.Leu830Arg (c.2489T>G) is associated with Inborn genetic diseases (ClinVar).

How common is HR p.Leu830Arg (c.2489T>G) in the general population?

HR p.Leu830Arg (c.2489T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HR p.Leu830Arg (c.2489T>G)?

AlphaMissense predicts likely benign (score 0.1415) — an in-silico prediction, not a clinical call.

HR p.Leu830Arg

c.2489T>G · VCV3526575

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1415 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1415	likely benign
REVEL	0.338	indeterminate
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.66, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 5,185 bp · p 0.0011 · regional, not allelic
Overall
CADD	22.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HR
Protein: p.Leu830Arg
Coding: c.2489T>G
MANE Select: NM_005144
Type: single nucleotide variant
Location: chr8:22120837 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HR p.Ala1188Asp Uncertain significance ★★ ⚠ same condition
HR p.Ala511Thr Uncertain significance ★★ ⚠ same condition
HR p.Ala555Thr Uncertain significance ★★ same condition
HR p.Ala900Thr Uncertain significance ★★ ⚠ same condition
HR p.Arg1095Trp Uncertain significance ★★ ⚠ same condition
HR p.Arg1096Gln Uncertain significance ★★ ⚠ same condition
HR p.Arg1097His Uncertain significance ★★ ⚠ same condition
HR p.Arg565Gln 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-leu830arg (accessed [today's date]).

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