Is HBD p.Phe119Val (c.355T>G) pathogenic?

HBD p.Phe119Val (c.355T>G) is classified Uncertain significance in HBD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.4818); Very rare (popmax 0.00133%, afr).

How common is HBD p.Phe119Val (c.355T>G) in the general population?

HBD p.Phe119Val (c.355T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about HBD p.Phe119Val (c.355T>G)?

AlphaMissense predicts ambiguous (score 0.4818) — an in-silico prediction, not a clinical call.

HBD p.Phe119Val

c.355T>G · VCV4033882

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4818 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4818	ambiguous
REVEL	0.733	pathogenic-leaning
SaProt	LLR -10.76	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -2.2
Regional constraint	o/e 1.08	unconstrained · MANE · 1,466 bp · p 0.27 · regional, not allelic
Overall
CADD	14.46	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 0.00133% African / African-American · 1/75,032 alleles

Overall 6.2e-05% 1/1,614,090 alleles · very rare exomes 1/1,461,778 · genomes 0/152,312 · 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.Phe119Val
Coding: c.355T>G
MANE Select: NM_000519
Type: single nucleotide variant
Location: chr11:5233053 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB
Residue 119: the globin domain; an α-helix

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

Similar variants

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
HBD c.93-28G>C 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-phe119val (accessed [today's date]).

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