Is HBB p.Ser10Cys (c.29C>G) pathogenic?

HBB p.Ser10Cys (c.29C>G) is classified Benign/Likely benign in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-15). AlphaMissense: likely benign (0.1736); Very rare (popmax 8.48e-05%, nfe).

How common is HBB p.Ser10Cys (c.29C>G) in the general population?

HBB p.Ser10Cys (c.29C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about HBB p.Ser10Cys (c.29C>G)?

AlphaMissense predicts likely benign (score 0.1736) — an in-silico prediction, not a clinical call.

HBB p.Ser10Cys

c.29C>G · rs33918131 · VCV15316

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1736	likely benign
REVEL	0.527	indeterminate
SaProt	LLR -9.30	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 -12	GERP -3.7
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	1.637	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 8.48e-05% European (non-Finnish) · 1/1,179,144 alleles

Overall 0.000124% 2/1,613,188 alleles · very rare exomes 2/1,460,866 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)grpmax	8.48e-05%	1,179,144

Remaining individuals 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: HBB
Protein: p.Ser10Cys
Coding: c.29C>G
MANE Select: NM_000518
dbSNP: rs33918131
Type: single nucleotide variant
Location: chr11:5226993 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 10: an α-helix; a modified residue (phosphoserine); the globin domain; a UniProt-annotated variant site (in porto alegre; o(2) affinity up)

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

Similar variants

HBB p.Ser10= Uncertain significance ★ same residue
HBB p.Ser10fs Pathogenic same residue
HBB c.316-146T>G Pathogenic ★★★ same type
HBB c.316-197C>T Pathogenic ★★★ same type
HBB c.92+5G>C Pathogenic ★★★ same type
HBB c.-78A>C Pathogenic ★★★ same type
HBB c.*111A>G Pathogenic ★★★ same type
HBB p.Ala28Ser Pathogenic ★★★ ⚠ same type

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-ser10cys (accessed [today's date]).

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