Is DLL3 p.Phe172Cys (c.515T>G) pathogenic?

DLL3 p.Phe172Cys (c.515T>G) is classified Benign in DLL3 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.9254); Common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele; Associated with leukodystrophy and acquired microcephaly with or without dystonia;.

What condition is associated with DLL3 p.Phe172Cys (c.515T>G)?

DLL3 p.Phe172Cys (c.515T>G) is associated with leukodystrophy and acquired microcephaly with or without dystonia;, spondylocostal dysostosis 1, autosomal recessive, syndactyly (ClinVar).

What do computational predictors say about DLL3 p.Phe172Cys (c.515T>G)?

AlphaMissense predicts likely pathogenic (score 0.9254) — an in-silico prediction, not a clinical call.

DLL3 p.Phe172Cys

Q: How common is DLL3 p.Phe172Cys (c.515T>G) in the general population?

DLL3 p.Phe172Cys (c.515T>G) is common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.515T>G · rs8107127 · VCV41378

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.9254 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 37.6%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

leukodystrophy and acquired microcephaly with or without dystonia;

Computational evidence

Protein change
AlphaMissense	0.9254	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -8.70	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 9,279 bp · p 0.0035 · regional, not allelic
Overall
CADD	22.7	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 37.6% Middle Eastern · 1,523/4,054 alleles

Filtering AF 36% ClinGen BA1/BS1 input FAF95, joint · FAF99 35.4%

Overall 32% 461,949/1,441,728 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	38.8%	3
Middle Easterngrpmax	37.6%	3
European (non-Finnish)	33.2%	3
South Asian	32.4%	3
Remaining individualsnot grpmax-eligible	31.5%	3
Amishnot grpmax-eligible	30.6%	3
Admixed American	28.6%	4
Ashkenazi Jewishnot grpmax-eligible	28.3%	4
African / African-American	22%	5
East Asian	11.3%	9

Finnish 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: DLL3
Protein: p.Phe172Cys
Coding: c.515T>G
dbSNP: rs8107127
Type: single nucleotide variant
Location: chr19:39502920 (GRCh38)

Full DLL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

leukodystrophy and acquired microcephaly with or without dystonia; — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spondylocostal dysostosis 1, autosomal recessive syndactyly

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/dll3-p-phe172cys (accessed [today's date]).

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