Is MLYCD p.Ser213Ile (c.638G>T) pathogenic?

MLYCD p.Ser213Ile (c.638G>T) is classified Uncertain significance in MLYCD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). AlphaMissense: likely pathogenic (0.5764); Very rare (popmax 8.5e-05%, nfe); Associated with malonic aciduria.

What condition is associated with MLYCD p.Ser213Ile (c.638G>T)?

MLYCD p.Ser213Ile (c.638G>T) is associated with malonic aciduria (ClinVar).

How common is MLYCD p.Ser213Ile (c.638G>T) in the general population?

MLYCD p.Ser213Ile (c.638G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

How is Malonic aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MLYCD p.Ser213Ile (c.638G>T)?

AlphaMissense predicts likely pathogenic (score 0.5764) — an in-silico prediction, not a clinical call.

MLYCD p.Ser213Ile

c.638G>T · rs1371831725 · VCV1993294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

malonic aciduria

Computational evidence

Protein change
AlphaMissense	0.5764	likely pathogenic
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.86	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 16 kb · p 1.5e-22 · regional, not allelic
Overall
CADD	25.9	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 8.5e-05% European (non-Finnish) · 1/1,176,390 alleles

Overall 0.000657% 1/152,226 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: MLYCD
Protein: p.Ser213Ile
Coding: c.638G>T
MANE Select: NM_012213
dbSNP: rs1371831725
Type: single nucleotide variant
Location: chr16:83907096 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.16 · 2 PDB
Residue 213: the 'catalytic domain' region; an α-helix

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

Disease context

malonic aciduria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Malonic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MLYCD p.Ser213Cys Uncertain significance ★ ⚠ same residue
MLYCD p.Ser213fs Pathogenic ★ same residue
MLYCD p.Ser187Ter Pathogenic ★★ same condition
MLYCD c.*218C>A Uncertain significance ★★ same condition
MLYCD p.Ala119Ser Uncertain significance ★★ ⚠ same condition
MLYCD p.Ala415Thr Uncertain significance ★★ ⚠ same condition
MLYCD p.Arg199Gln Uncertain significance ★★ ⚠ same condition
MLYCD p.Arg235Gly 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/mlycd-p-ser213ile (accessed [today's date]).

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