Is MEF2C p.Pro167Ser (c.499C>T) pathogenic?

MEF2C p.Pro167Ser (c.499C>T) is classified Benign in MEF2C (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00223%, eas); Associated with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language.

How common is MEF2C p.Pro167Ser (c.499C>T) in the general population?

MEF2C p.Pro167Ser (c.499C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MEF2C p.Pro167Ser (c.499C>T)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

MEF2C p.Pro167Ser

Q: What condition is associated with MEF2C p.Pro167Ser (c.499C>T)?

MEF2C p.Pro167Ser (c.499C>T) is associated with neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (ClinVar).

c.499C>T · rs1322552264 · VCV1357578

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.55	unconstrained · MANE · 39 kb · p 1.1e-22 · regional, not allelic
Overall
CADD	21.9	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 0.00223% East Asian · 1/44,902 alleles

Overall 0.00031% 5/1,613,866 alleles · very rare exomes 3/1,461,680 · genomes 2/152,186 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,342
East Asiangrpmax	0.00223%	44,902
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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: MEF2C
Protein: p.Pro167Ser
Coding: c.499C>T
MANE Select: NM_002397
dbSNP: rs1322552264
Type: single nucleotide variant
Location: chr5:88751947 (GRCh38)
Gene constraint: LOEUF 0.212 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.80

Full MEF2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEF2C p.Pro167= Likely benign ★ same residue
MEF2C c.638-1G>A Pathogenic/Likely pathogenic ★★ same condition
MEF2C c.638-2A>C Pathogenic ★★ same condition
MEF2C c.965-2A>G Pathogenic ★★ same condition
MEF2C c.-26C>T Pathogenic ★★ same condition
MEF2C c.-8C>T Pathogenic ★★ same condition
MEF2C p.Arg15Cys Pathogenic/Likely pathogenic ★★ same condition
MEF2C p.Arg15His Pathogenic/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/mef2c-p-pro167ser (accessed [today's date]).

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