Is DERL3 p.Arg83Pro (c.248G>C) pathogenic?

DERL3 p.Arg83Pro (c.248G>C) is classified Uncertain significance in DERL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-23). AlphaMissense: likely pathogenic (0.9422); Very rare (popmax 0.00339%, amr).

How common is DERL3 p.Arg83Pro (c.248G>C) in the general population?

DERL3 p.Arg83Pro (c.248G>C) is very rare (popmax 0.00339%, amr) (gnomAD).

What do computational predictors say about DERL3 p.Arg83Pro (c.248G>C)?

AlphaMissense predicts likely pathogenic (score 0.9422) — an in-silico prediction, not a clinical call.

DERL3 p.Arg83Pro

c.248G>C · VCV3271651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9422	likely pathogenic · top 6% in DERL3
REVEL	0.665	pathogenic-leaning
SaProt	LLR -17.46	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 5.9	GERP 0.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,115 bp · p 0.39 · regional, not allelic
Overall
CADD	33.0	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 0.00339% Admixed American · 2/58,940 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000974%

Overall 0.0015% 24/1,604,442 alleles · very rare exomes 23/1,452,262 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00339%	29,470
European (non-Finnish)	0.00179%	55,972
African / African-American	0.00134%	74,582

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: DERL3
Protein: p.Arg83Pro
Coding: c.248G>C
MANE Select: NM_001002862
Type: single nucleotide variant
Location: chr22:23838431 (GRCh38)
Gene constraint: LOEUF 1.414 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.33

Full DERL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DERL3 p.Ala177= Benign/Likely benign ★★ same type
SMARCB1 c.*362T>G Likely benign ★★ same type
DERL3 p.Ala8Asp Uncertain significance ★ ⚠ same type
DERL3 p.Arg93His Uncertain significance ★ ⚠ same type
DERL3 p.Asn142Ser Uncertain significance ★ ⚠ same type
DERL3 p.Asn74Ile Uncertain significance ★ ⚠ same type
DERL3 p.Asp96Glu Uncertain significance ★ ⚠ same type
DERL3 p.His180Arg 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/derl3-p-arg83pro (accessed [today's date]).

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