Is HR p.Pro283Ser (c.847C>T) pathogenic?

HR p.Pro283Ser (c.847C>T) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely benign (0.0698); Ultra-rare (popmax 0.0758%, eas); Associated with Inborn genetic diseases.

What condition is associated with HR p.Pro283Ser (c.847C>T)?

HR p.Pro283Ser (c.847C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HR p.Pro283Ser (c.847C>T) in the general population?

HR p.Pro283Ser (c.847C>T) is ultra-rare (popmax 0.0758%, eas) (gnomAD).

What do computational predictors say about HR p.Pro283Ser (c.847C>T)?

AlphaMissense predicts likely benign (score 0.0698) — an in-silico prediction, not a clinical call.

HR p.Pro283Ser

c.847C>T · rs138592607 · VCV2408948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0758%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0698	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.72	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 2.2	GERP -0.49, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	15.82	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 0.0758% East Asian · 34/44,862 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.00323% 52/1,612,004 alleles · ultra-rare exomes 46/1,459,652 · genomes 6/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0758%	1,319
Remaining individualsnot grpmax-eligible	0.0064%	15,615
Admixed American	0.00167%	60,028
European (non-Finnish)	0.0011%	90,750

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.Pro283Ser
Coding: c.847C>T
MANE Select: NM_005144
dbSNP: rs138592607
Type: single nucleotide variant
Location: chr8:22127595 (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-pro283ser (accessed [today's date]).

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