Is DNAJB8 p.Leu48Pro (c.143T>C) pathogenic?

DNAJB8 p.Leu48Pro (c.143T>C) is classified Uncertain significance in DNAJB8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-06). AlphaMissense: likely pathogenic (0.856); Ultra-rare (popmax 0.0849%, amr).

How common is DNAJB8 p.Leu48Pro (c.143T>C) in the general population?

DNAJB8 p.Leu48Pro (c.143T>C) is ultra-rare (popmax 0.0849%, amr) (gnomAD).

What do computational predictors say about DNAJB8 p.Leu48Pro (c.143T>C)?

AlphaMissense predicts likely pathogenic (score 0.856) — an in-silico prediction, not a clinical call.

DNAJB8 p.Leu48Pro

c.143T>C · rs201743640 · VCV3084420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0849%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.856	likely pathogenic
REVEL	0.199	benign-leaning
SaProt	LLR -12.84	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.94, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 695 bp · p 0.049 · regional, not allelic
Overall
CADD	23.5	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 0.0849% Admixed American · 51/60,036 alleles

Filtering AF 0.0663% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0597%

Overall 0.00421% 68/1,614,226 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0849%	1,177
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.00133%	75,054
European (non-Finnish)	0.000932%	107,277

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: DNAJB8
Protein: p.Leu48Pro
Coding: c.143T>C
MANE Select: NM_153330
dbSNP: rs201743640
Type: single nucleotide variant
Location: chr3:128463103 (GRCh38)
Gene constraint: LOEUF 1.786 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 66.35 · 2 PDB
Residue 48: the j domain; an α-helix

Full DNAJB8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJB8 p.Glu6= Benign ★★ same type
DNAJB8 p.Met153Leu Benign ★★ same type
DNAJB8 p.Ala143Asp Uncertain significance ★ ⚠ same type
DNAJB8 p.Ala143Gly Uncertain significance ★ ⚠ same type
DNAJB8 p.Ala147Val Uncertain significance ★ ⚠ same type
DNAJB8 p.Ala68Thr Uncertain significance ★ ⚠ same type
DNAJB8 p.Arg131Ser Uncertain significance ★ ⚠ same type
DNAJB8 p.Arg206His 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/dnajb8-p-leu48pro (accessed [today's date]).

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