Is CECR2 p.Phe1418Leu (c.4254C>G) pathogenic?

CECR2 p.Phe1418Leu (c.4254C>G) is classified Uncertain significance in CECR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.68); Very rare (popmax 8.53e-05%, nfe); Associated with CECR2-related neurodevelopmental disorder.

What condition is associated with CECR2 p.Phe1418Leu (c.4254C>G)?

CECR2 p.Phe1418Leu (c.4254C>G) is associated with CECR2-related neurodevelopmental disorder (ClinVar).

How common is CECR2 p.Phe1418Leu (c.4254C>G) in the general population?

CECR2 p.Phe1418Leu (c.4254C>G) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about CECR2 p.Phe1418Leu (c.4254C>G)?

AlphaMissense predicts likely pathogenic (score 0.68) — an in-silico prediction, not a clinical call.

CECR2 p.Phe1418Leu

c.4254C>G · VCV4073550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.68 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CECR2-related neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.68	likely pathogenic
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.39	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 1.7	GERP 0.45, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 12 kb · p 0.093 · regional, not allelic
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F1438L vs ClinVar F1418L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.53e-05% European (non-Finnish) · 1/1,171,994 alleles

Overall 6.92e-05% 1/1,444,970 alleles · very rare

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: CECR2
Protein: p.Phe1418Leu
Coding: c.4254C>G
MANE Select: NM_001290047
Type: single nucleotide variant
Location: chr22:17549541 (GRCh38)
Gene constraint: LOEUF 0.259 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 50.01 · 3 PDB

Full CECR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CECR2-related neurodevelopmental disorder

Similar variants

CECR2 p.Arg607Ter Likely pathogenic ★ same condition
CECR2 p.Gln1385Glu Likely pathogenic ★ ⚠ same condition
CECR2 p.Arg761Ter Conflicting classifications of pathogenicity ★ ⚠ same condition
CECR2 p.Gln1428Arg Uncertain significance ★ ⚠ same condition
CECR2 p.Thr580fs Likely pathogenic ★ same condition
CECR2 c.955-8C>T Benign ★★ same type
CECR2 p.Ala743Val Benign ★★ same type
CECR2 p.Ala847= Benign ★★ 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/cecr2-p-phe1418leu (accessed [today's date]).

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