Is DERL3 p.Phe49Leu (c.147C>G) pathogenic?

DERL3 p.Phe49Leu (c.147C>G) is classified Uncertain significance in DERL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-18). AlphaMissense: likely pathogenic (0.5953); Ultra-rare (popmax 0.0171%, eas).

How common is DERL3 p.Phe49Leu (c.147C>G) in the general population?

DERL3 p.Phe49Leu (c.147C>G) is ultra-rare (popmax 0.0171%, eas) (gnomAD).

What do computational predictors say about DERL3 p.Phe49Leu (c.147C>G)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

DERL3 p.Phe49Leu

c.147C>G · VCV3271649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 0.65, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,115 bp · p 0.39 · regional, not allelic
Overall
CADD	22.9	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 0.0171% East Asian · 7/40,932 alleles

Filtering AF 0.00798% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00564%

Overall 0.000516% 8/1,550,692 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0171%	5,847
Remaining individualsnot grpmax-eligible	0.00167%	60,030

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.Phe49Leu
Coding: c.147C>G
MANE Select: NM_001002862
Type: single nucleotide variant
Location: chr22:23838723 (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.Arg83Pro 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

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-phe49leu (accessed [today's date]).

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