Is HBD p.Ala28Ser (c.82G>T) pathogenic?

HBD p.Ala28Ser (c.82G>T) is classified Conflicting classifications of pathogenicity in HBD (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.2001); Rare (popmax 0.643%, mid); Associated with Fetal hemoglobin quantitative trait locus 1.

What condition is associated with HBD p.Ala28Ser (c.82G>T)?

HBD p.Ala28Ser (c.82G>T) is associated with Fetal hemoglobin quantitative trait locus 1, thalassemia, glucocorticoid-remediable aldosteronism (ClinVar).

How common is HBD p.Ala28Ser (c.82G>T) in the general population?

HBD p.Ala28Ser (c.82G>T) is rare (popmax 0.643%, mid) (gnomAD).

What do computational predictors say about HBD p.Ala28Ser (c.82G>T)?

AlphaMissense predicts likely benign (score 0.2001) — an in-silico prediction, not a clinical call.

HBD p.Ala28Ser

c.82G>T · rs35152987 · VCV15070

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2001 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.643%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Fetal hemoglobin quantitative trait locus 1

Computational evidence

Protein change
AlphaMissense	0.2001	likely benign
REVEL	0.636	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.67	donor gain · deltas
Pangolin	Δ0.60	gain · loss 0.32 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Regional constraint	o/e 1.08	unconstrained · MANE · 1,466 bp · p 0.27 · regional, not allelic
Overall
CADD	19.23	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 0.643% Middle Eastern · 39/6,062 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.428%

Overall 0.187% 3,024/1,613,812 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.753%	133
Middle Easterngrpmax	0.643%	155
South Asian	0.395%	253
Remaining individualsnot grpmax-eligible	0.23%	434
European (non-Finnish)	0.176%	569
Finnishnot grpmax-eligible	0.125%	800
Admixed American	0.118%	845
African / African-American	0.0427%	2,344

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: HBD
Protein: p.Ala28Ser
Coding: c.82G>T
MANE Select: NM_000519
dbSNP: rs35152987
Type: single nucleotide variant
Location: chr11:5234352 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 28: the globin domain; a UniProt-annotated variant site (in yialousa); an α-helix

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

Disease context

Fetal hemoglobin quantitative trait locus 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: thalassemia glucocorticoid-remediable aldosteronism

Similar variants

HBD p.Ala28Asp Uncertain significance ★ ⚠ same residue
HBD p.Gly75= Uncertain significance ★★ same condition
HBD p.Thr5Ile Uncertain significance ★★ ⚠ same condition
HBD c.*59C>G Uncertain significance ★ same condition
HBD c.*65T>C Uncertain significance ★ same condition
HBD c.*91G>A Uncertain significance ★ same condition
HBD c.*96G>T Uncertain significance ★ same condition
HBD p.Arg117Cys 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/hbd-p-ala28ser (accessed [today's date]).

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