Is NDE1 p.Ser291Phe (c.872C>T) pathogenic?

NDE1 p.Ser291Phe (c.872C>T) is classified Conflicting classifications of pathogenicity in NDE1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0998); Rare (popmax 0.346%, mid); Associated with lissencephaly 4.

What condition is associated with NDE1 p.Ser291Phe (c.872C>T)?

NDE1 p.Ser291Phe (c.872C>T) is associated with lissencephaly 4, intellectual disability, NDE1-related microhydranencephaly (ClinVar).

How common is NDE1 p.Ser291Phe (c.872C>T) in the general population?

NDE1 p.Ser291Phe (c.872C>T) is rare (popmax 0.346%, mid) (gnomAD).

What do computational predictors say about NDE1 p.Ser291Phe (c.872C>T)?

AlphaMissense predicts likely benign (score 0.0998) — an in-silico prediction, not a clinical call.

NDE1 p.Ser291Phe

c.872C>T · rs146284370 · VCV159020

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0998 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.346%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lissencephaly 4

Computational evidence

Protein change
AlphaMissense	0.0998	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.8	GERP 1.1, phastCons 0.007
Regional constraint	o/e 1.02	unconstrained · MANE · 59 kb · p 0.74 · regional, not allelic
Overall
CADD	19.4	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 0.346% Middle Eastern · 21/6,062 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0515% 832/1,614,226 alleles · rare exomes 748/1,461,890 · genomes 84/152,336 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.346%	289
South Asian	0.0856%	1,168
Admixed American	0.0766%	1,305
Remaining individualsnot grpmax-eligible	0.0688%	1,454
European (non-Finnish)	0.053%	1,885
African / African-American	0.0173%	5,775
Finnishnot grpmax-eligible	0.00625%	16,011
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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: NDE1
Protein: p.Ser291Phe
Coding: c.872C>T
MANE Select: NM_017668
dbSNP: rs146284370
Type: single nucleotide variant
Location: chr16:15696785 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.40 · 1 PDB
Residue 291: the 'disordered' region

Full NDE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lissencephaly 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: intellectual disability NDE1-related microhydranencephaly

Similar variants

NDE1 p.Arg220Ter Pathogenic/Likely pathogenic ★★ same condition
NDE1 p.Arg37Ter Pathogenic ★★ same condition
MYH11 p.Glu1344Val Uncertain significance ★★ ⚠ same condition
NDE1 p.Ala101Val Uncertain significance ★★ ⚠ same condition
NDE1 p.Ala208Val Uncertain significance ★★ ⚠ same condition
NDE1 p.Arg234His Uncertain significance ★★ ⚠ same condition
NDE1 p.Arg275Trp Uncertain significance ★★ ⚠ same condition
NDE1 p.Arg62Gly Uncertain significance ★★ ⚠ same condition

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/nde1-p-ser291phe (accessed [today's date]).

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