Is HBB p.Pro6Ala (c.16C>G) pathogenic?

HBB p.Pro6Ala (c.16C>G) is classified Likely benign in HBB (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-21). AlphaMissense: likely benign (0.0367); Very rare (popmax 0.00119%, nfe).

How common is HBB p.Pro6Ala (c.16C>G) in the general population?

HBB p.Pro6Ala (c.16C>G) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about HBB p.Pro6Ala (c.16C>G)?

AlphaMissense predicts likely benign (score 0.0367) — an in-silico prediction, not a clinical call.

HBB p.Pro6Ala

c.16C>G · rs33912272 · VCV1331036

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0367 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0367	likely benign
REVEL	0.464	indeterminate
SaProt	LLR -5.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -0.85
Regional constraint	o/e 0.88	unconstrained · MANE · 1,420 bp · p 0.11 · regional, not allelic
Overall
CADD	0.081	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 0.00119% European (non-Finnish) · 14/1,176,250 alleles

Filtering AF 0.000691% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00054%

Overall 0.00087% 14/1,609,894 alleles · very rare exomes 13/1,457,722 · genomes 1/152,172 · joint denominator

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.Pro6Ala
Coding: c.16C>G
MANE Select: NM_000518
dbSNP: rs33912272
Type: single nucleotide variant
Location: chr11:5227006 (GRCh38)
Gene constraint: LOEUF 1.964 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.09 · 350 PDB
Residue 6: an α-helix; the globin domain; a UniProt-annotated variant site (in warwickshire)

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

Similar variants

HBB p.Pro6Ser Uncertain significance ★★ ⚠ same residue
HBB p.Pro6= Likely benign ★ same residue
HBB p.Pro6_Glu7delinsSerTer 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

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-pro6ala (accessed [today's date]).

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