Is HBB p.Pro37His (c.110C>A) pathogenic?

HBB p.Pro37His (c.110C>A) is classified Conflicting classifications of pathogenicity in HBB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-09-14). AlphaMissense: likely pathogenic (0.9502); Absent from gnomAD v4.1; Associated with hypertrophic cardiomyopathy 26.

What condition is associated with HBB p.Pro37His (c.110C>A)?

HBB p.Pro37His (c.110C>A) is associated with hypertrophic cardiomyopathy 26, erythrocytosis, familial, 6 (ClinVar).

How common is HBB p.Pro37His (c.110C>A) in the general population?

HBB p.Pro37His (c.110C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HBB p.Pro37His (c.110C>A)?

AlphaMissense predicts likely pathogenic (score 0.9502) — an in-silico prediction, not a clinical call.

HBB p.Pro37His

c.110C>A · rs33993004 · VCV15578

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9502 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
AlphaMissense	0.9502	likely pathogenic
REVEL	0.966	strongly pathogenic-leaning
SaProt	LLR -14.74	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	25.8	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

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: HBB
Protein: p.Pro37His
Coding: c.110C>A
MANE Select: NM_000518
dbSNP: rs33993004
Type: single nucleotide variant
Location: chr11:5226782 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 37: a UniProt-annotated variant site (in sunnybrook); a UniProt-annotated variant site (in north chicago; o(2) affinity up); a UniProt-annotated variant site (in linkoping/finlandia; o(2) affinity up); a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain

Full HBB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 26 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: erythrocytosis, familial, 6

Similar variants

HBB p.Pro37Thr Pathogenic ★ same residue
HBB p.Pro37= Likely benign ★ same residue
HBB c.316-197C>T Pathogenic ★★★ same condition
HBB c.92+5G>C Pathogenic ★★★ same condition
HBB c.-78A>C Pathogenic ★★★ same condition
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same condition
HBB p.Lys18Ter Pathogenic ★★★ same condition
HBB c.-75G>C 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/hbb-p-pro37his (accessed [today's date]).

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