Is MECP2 p.Pro397His (c.1190C>A) pathogenic?

MECP2 p.Pro397His (c.1190C>A) is classified Likely benign in MECP2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-10-09). AlphaMissense: likely benign (0.0893); Very rare (popmax 0.00651%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MECP2 p.Pro397His (c.1190C>A)?

MECP2 p.Pro397His (c.1190C>A) is associated with Inborn genetic diseases, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro397His (c.1190C>A) in the general population?

MECP2 p.Pro397His (c.1190C>A) is very rare (popmax 0.00651%, nfe) (gnomAD).

What do computational predictors say about MECP2 p.Pro397His (c.1190C>A)?

AlphaMissense predicts likely benign (score 0.0893) — an in-silico prediction, not a clinical call.

MECP2 p.Pro397His

c.1190C>A · rs111302745 · VCV156631

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00651%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0893	likely benign
REVEL	0.468	indeterminate
SaProt	LLR -10.70	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP -0.67, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	18.01	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 P385H vs ClinVar P397H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00651% European (non-Finnish) · 58/891,130 alleles

Filtering AF 0.00511% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.005% 60/1,199,903 alleles · very rare exomes 56/1,090,661 · genomes 4/109,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00651%	15,364
Ashkenazi Jewishnot grpmax-eligible	0.00456%	21,932
African / African-American	0.00178%	56,228

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: MECP2
Protein: p.Pro397His
Coding: c.1190C>A
MANE Select: NM_001110792
dbSNP: rs111302745
Type: single nucleotide variant
Location: chrX:154030674 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 385 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly

Similar variants

MECP2 p.Pro397Ser Likely benign ★★★ same residue
MECP2 p.Pro397= Likely benign ★★ same residue
MECP2 p.Pro397Arg Uncertain significance ★ ⚠ same residue
MECP2 p.Pro397Leu Likely benign ★ same residue
MECP2 p.Pro397Thr Likely benign ★ ⚠ same residue
MECP2 p.Pro397fs Pathogenic/Likely pathogenic ★★ same residue
MECP2 p.Pro397_Pro403del Uncertain significance ★★ same residue
MECP2 p.Pro397_Glu409delinsGlnGlnAsnSerProProTer Pathogenic ★ same residue

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/mecp2-p-pro397his (accessed [today's date]).

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