Is DEFB1 p.Phe52Val (c.154T>G) pathogenic?

DEFB1 p.Phe52Val (c.154T>G) is classified Uncertain significance in DEFB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.6731); Ultra-rare (popmax 0.0267%, amr).

How common is DEFB1 p.Phe52Val (c.154T>G) in the general population?

DEFB1 p.Phe52Val (c.154T>G) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about DEFB1 p.Phe52Val (c.154T>G)?

AlphaMissense predicts likely pathogenic (score 0.6731) — an in-silico prediction, not a clinical call.

DEFB1 p.Phe52Val

c.154T>G · VCV3271449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6731	likely pathogenic
REVEL	0.09	moderately benign-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -3.4
Regional constraint	o/e 2.11	unconstrained · MANE · 7,173 bp · p 2.7e-22 · regional, not allelic
Overall
CADD	2.622	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 0.0267% Admixed American · 16/60,006 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00378% 61/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
East Asian	0.0156%	6,414
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.0028%	35,759

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: DEFB1
Protein: p.Phe52Val
Coding: c.154T>G
MANE Select: NM_005218
Type: single nucleotide variant
Location: chr8:6870734 (GRCh38)
Gene constraint: LOEUF 1.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.82 · 15 PDB
Residue 52: a disulfide bond

Full DEFB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB1 p.Gly27= Benign ★★ same type
DEFB1 p.Ala19Thr Uncertain significance ★ ⚠ same type
DEFB1 p.Ala64Gly Uncertain significance ★ ⚠ same type
DEFB1 p.Asp33Gly Uncertain significance ★ ⚠ same type
DEFB1 p.Cys12Phe Uncertain significance ★ ⚠ same type
DEFB1 p.Cys44Tyr Uncertain significance ★ ⚠ same type
DEFB1 p.Cys59Tyr Uncertain significance ★ ⚠ same type
DEFB1 p.Gly57Ala 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/defb1-p-phe52val (accessed [today's date]).

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