Is DERA p.Pro23Leu (c.68C>T) pathogenic?

DERA p.Pro23Leu (c.68C>T) is classified Uncertain significance in DERA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely benign (0.1867); Ultra-rare (popmax 0.02%, afr).

How common is DERA p.Pro23Leu (c.68C>T) in the general population?

DERA p.Pro23Leu (c.68C>T) is ultra-rare (popmax 0.02%, afr) (gnomAD).

What do computational predictors say about DERA p.Pro23Leu (c.68C>T)?

AlphaMissense predicts likely benign (score 0.1867) — an in-silico prediction, not a clinical call.

DERA p.Pro23Leu

c.68C>T · VCV4659634

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1867	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 125 kb · p 0.71 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.02% African / African-American · 15/74,908 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00989%

Overall 0.00266% 43/1,613,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.02%	4,994
Admixed American	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0032%	31,230
South Asian	0.0022%	45,541
Finnishnot grpmax-eligible	0.00156%	63,996
European (non-Finnish)	0.0011%	90,758

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.Pro23Leu
Coding: c.68C>T
MANE Select: NM_015954
Type: single nucleotide variant
Location: chr12:15956972 (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.Pro23Ser 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-pro23leu (accessed [today's date]).

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