Is MECP2 p.Ser371Pro (c.1111T>C) pathogenic?

MECP2 p.Ser371Pro (c.1111T>C) is classified Benign/Likely benign in MECP2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0849); Ultra-rare (popmax 0.0416%, amr); Associated with Inborn genetic diseases.

What condition is associated with MECP2 p.Ser371Pro (c.1111T>C)?

MECP2 p.Ser371Pro (c.1111T>C) is associated with Inborn genetic diseases, severe neonatal-onset encephalopathy with microcephaly, Rett syndrome (ClinVar).

How common is MECP2 p.Ser371Pro (c.1111T>C) in the general population?

MECP2 p.Ser371Pro (c.1111T>C) is ultra-rare (popmax 0.0416%, amr) (gnomAD).

What do computational predictors say about MECP2 p.Ser371Pro (c.1111T>C)?

AlphaMissense predicts likely benign (score 0.0849) — an in-silico prediction, not a clinical call.

MECP2 p.Ser371Pro

c.1111T>C · rs61752371 · VCV143321

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0849 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0416%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0849	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -1, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	17.54	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 S359P vs ClinVar S371P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0416% Admixed American · 19/45,642 alleles

Filtering AF 0.0272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0226%

Overall 0.0053% 64/1,207,825 alleles · ultra-rare exomes 59/1,097,604 · genomes 5/110,221 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0416%	2,402
Middle Eastern	0.023%	4,346
Remaining individualsnot grpmax-eligible	0.00631%	15,846
European (non-Finnish)	0.00447%	22,358
South Asian	0.00176%	56,685

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.Ser371Pro
Coding: c.1111T>C
MANE Select: NM_001110792
dbSNP: rs61752371
Type: single nucleotide variant
Location: chrX:154030753 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 359 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in)

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 Rett syndrome

Similar variants

MECP2 p.Ser371Ala Uncertain significance ★ ⚠ same residue
MECP2 p.Ser371= Likely benign ★ same residue
MECP2 p.Ser371Phe Uncertain significance ★ ⚠ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 c.62+2T>G Pathogenic ★★★ same condition
MECP2 p.Ala143Asp Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ 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/mecp2-p-ser371pro (accessed [today's date]).

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