Is HBB p.Thr88Pro (c.262A>C) pathogenic?

HBB p.Thr88Pro (c.262A>C) is classified Benign/Likely benign in HBB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-20). AlphaMissense: likely benign (0.1258); Ultra-rare (popmax 0.0164%, mid); Associated with hereditary persistence of fetal hemoglobin.

What condition is associated with HBB p.Thr88Pro (c.262A>C)?

HBB p.Thr88Pro (c.262A>C) is associated with hereditary persistence of fetal hemoglobin, Heinz body anemia, dominant beta-thalassemia (ClinVar).

How common is HBB p.Thr88Pro (c.262A>C) in the general population?

HBB p.Thr88Pro (c.262A>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about HBB p.Thr88Pro (c.262A>C)?

AlphaMissense predicts likely benign (score 0.1258) — an in-silico prediction, not a clinical call.

HBB p.Thr88Pro

c.262A>C · rs35553496 · VCV15489

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1258 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary persistence of fetal hemoglobin

Computational evidence

Protein change
AlphaMissense	0.1258	likely benign
REVEL	0.496	indeterminate
SaProt	LLR -5.56	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 -8.2	GERP -3.6
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	1.541	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00607% 98/1,613,996 alleles · ultra-rare exomes 95/1,461,842 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00797%	12,553
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: HBB
Protein: p.Thr88Pro
Coding: c.262A>C
MANE Select: NM_000518
dbSNP: rs35553496
Type: single nucleotide variant
Location: chr11:5226630 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 88: a UniProt-annotated variant site (in quebec-chori); a UniProt-annotated variant site (in d-ibadan); a UniProt-annotated variant site (in valletta); an α-helix; the globin domain; a modified residue (phosphothreonine)

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

Disease context

hereditary persistence of fetal hemoglobin — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Heinz body anemia dominant beta-thalassemia sickle cell disease alpha thalassemia spectrum beta-thalassemia HBB/LCRB beta thalassemia malaria, susceptibility to erythrocytosis, familial, 6

Similar variants

HBB p.Thr88Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
HBB p.Thr88Ile Likely pathogenic ★ ⚠ same residue
HBB c.316-146T>G Pathogenic ★★★ same condition
HBB c.316-197C>T Pathogenic ★★★ same condition
HBB c.92+5G>C Pathogenic ★★★ same condition
HBB c.-78A>C Pathogenic ★★★ same condition
HBB c.*111A>G Pathogenic ★★★ same condition
HBB p.Ala28Ser Pathogenic ★★★ ⚠ 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-thr88pro (accessed [today's date]).

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