Is DERA p.Trp42Cys (c.126G>T) pathogenic?

DERA p.Trp42Cys (c.126G>T) is classified Uncertain significance in DERA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely pathogenic (0.5943); Very rare (popmax 0.00246%, nfe).

How common is DERA p.Trp42Cys (c.126G>T) in the general population?

DERA p.Trp42Cys (c.126G>T) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about DERA p.Trp42Cys (c.126G>T)?

AlphaMissense predicts likely pathogenic (score 0.5943) — an in-silico prediction, not a clinical call.

DERA p.Trp42Cys

c.126G>T · rs375606723 · VCV2522948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5943 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5943	likely pathogenic
REVEL	0.426	indeterminate
SaProt	LLR -10.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 125 kb · p 0.71 · regional, not allelic
Overall
CADD	31.0	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 0.00246% European (non-Finnish) · 29/1,179,216 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00186% 30/1,613,036 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594
European (non-Finnish)grpmax	0.00246%	40,663

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DERA
Protein: p.Trp42Cys
Coding: c.126G>T
MANE Select: NM_015954
dbSNP: rs375606723
Type: single nucleotide variant
Location: chr12:15957030 (GRCh38)
Gene constraint: LOEUF 0.658 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 95.99

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

Similar variants

DERA p.Trp42Arg Uncertain significance ★ ⚠ same residue
DERA p.Ala115Ser Uncertain significance ★ ⚠ same type
DERA p.Ala131Thr Uncertain significance ★ ⚠ same type
DERA p.Ala228Gly Uncertain significance ★ ⚠ same type
DERA p.Ala262Val Uncertain significance ★ ⚠ same type
DERA p.Ala29Val Uncertain significance ★ ⚠ same type
DERA p.Arg105Gly Uncertain significance ★ ⚠ same type
DERA p.Arg105Trp 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/dera-p-trp42cys (accessed [today's date]).

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