Is HR p.Pro40Ser (c.118C>T) pathogenic?

HR p.Pro40Ser (c.118C>T) is classified Uncertain significance in HR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely benign (0.0644); Very rare (popmax 0.00337%, sas); Associated with Inborn genetic diseases.

What condition is associated with HR p.Pro40Ser (c.118C>T)?

HR p.Pro40Ser (c.118C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HR p.Pro40Ser (c.118C>T) in the general population?

HR p.Pro40Ser (c.118C>T) is very rare (popmax 0.00337%, sas) (gnomAD).

What do computational predictors say about HR p.Pro40Ser (c.118C>T)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

HR p.Pro40Ser

c.118C>T · rs544241017 · VCV2481782

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00337%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -6.37	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 0.15	GERP -2.8, phastCons 0.003
Regional constraint	o/e 1.00	unconstrained · MANE · 8,242 bp · p 0.98 · regional, not allelic
Overall
CADD	5.846	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 0.00337% South Asian · 3/88,904 alleles

Filtering AF 0.000896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000449%

Overall 0.000501% 8/1,598,074 alleles · very rare exomes 8/1,445,744 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00337%	29,635
European (non-Finnish)	0.000427%	234,326

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.Pro40Ser
Coding: c.118C>T
MANE Select: NM_005144
dbSNP: rs544241017
Type: single nucleotide variant
Location: chr8:22129053 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.65
Residue 40: the 'disordered' region

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.Pro40Gln Uncertain significance ★★ ⚠ same residue
HR p.Pro40= Uncertain significance ★ same residue
HR p.Pro40Leu Benign same residue
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

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-pro40ser (accessed [today's date]).

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