Is DNAJB1 p.Ser186Phe (c.557C>T) pathogenic?

DNAJB1 p.Ser186Phe (c.557C>T) is classified Uncertain significance in DNAJB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-22). AlphaMissense: likely pathogenic (0.7929); Very rare (popmax 0.00136%, nfe).

How common is DNAJB1 p.Ser186Phe (c.557C>T) in the general population?

DNAJB1 p.Ser186Phe (c.557C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about DNAJB1 p.Ser186Phe (c.557C>T)?

AlphaMissense predicts likely pathogenic (score 0.7929) — an in-silico prediction, not a clinical call.

DNAJB1 p.Ser186Phe

c.557C>T · VCV4661243

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7929	likely pathogenic
REVEL	0.713	pathogenic-leaning
SaProt	LLR -12.02	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 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 2,406 bp · p 0.0059 · regional, not allelic
Overall
CADD	27.5	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 0.00136% European (non-Finnish) · 16/1,180,040 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00105% 17/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00136%	73,752
African / African-American	0.00133%	74,918

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: DNAJB1
Protein: p.Ser186Phe
Coding: c.557C>T
MANE Select: NM_006145
Type: single nucleotide variant
Location: chr19:14516701 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.71 · 15 PDB
Residue 186: a β-strand

Full DNAJB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJB1 p.Asn272= Benign ★★ same type
DNAJB1 p.Val288= Benign ★★ same type
DNAJB1 p.Ala265Val Uncertain significance ★ ⚠ same type
DNAJB1 p.Arg119Gln Uncertain significance ★ ⚠ same type
DNAJB1 p.Arg13Cys Uncertain significance ★ ⚠ same type
DNAJB1 p.Arg26Leu Uncertain significance ★ ⚠ same type
DNAJB1 p.Arg290Ser Uncertain significance ★ ⚠ same type
DNAJB1 p.Arg294Trp 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/dnajb1-p-ser186phe (accessed [today's date]).

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