Is HBD p.Val35Asp (c.104T>A) pathogenic?

HBD p.Val35Asp (c.104T>A) is classified Uncertain significance in HBD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-15). AlphaMissense: likely pathogenic (0.9824); Very rare (popmax 6.2e-05%).

How common is HBD p.Val35Asp (c.104T>A) in the general population?

HBD p.Val35Asp (c.104T>A) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about HBD p.Val35Asp (c.104T>A)?

AlphaMissense predicts likely pathogenic (score 0.9824) — an in-silico prediction, not a clinical call.

HBD p.Val35Asp

c.104T>A · rs2494308091 · VCV2360148

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9824	likely pathogenic · top 9% in HBD
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.15	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 5.6	GERP 0.66, phastCons 0.96
Regional constraint	o/e 1.08	unconstrained · MANE · 1,466 bp · p 0.27 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.2e-05%

Overall 6.2e-05% 1/1,613,996 alleles · very rare exomes 1/1,461,710 · genomes 0/152,286 · 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: HBD
Protein: p.Val35Asp
Coding: c.104T>A
MANE Select: NM_000519
dbSNP: rs2494308091
Type: single nucleotide variant
Location: chr11:5234202 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 35: the globin domain; an α-helix

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

Similar variants

HBD p.Val35Ile Uncertain significance ★ ⚠ same residue
HBD p.Gly75= Uncertain significance ★★ same type
HBD p.Thr5Ile Uncertain significance ★★ ⚠ same type
HBD c.315+146T>G Benign ★★ same type
HBD p.His98= Benign ★★ same type
HBD c.316-2A>G Pathogenic ★ same type
HBD p.Gly137Asp Pathogenic ★ ⚠ same type
HBD c.316-5C>T Uncertain significance ★ 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/hbd-p-val35asp (accessed [today's date]).

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