Is MLYCD p.Ser358Trp (c.1073C>G) pathogenic?

MLYCD p.Ser358Trp (c.1073C>G) is classified Uncertain significance in MLYCD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). AlphaMissense: likely benign (0.1684); Ultra-rare (popmax 0.0176%, sas); Associated with malonic aciduria.

What condition is associated with MLYCD p.Ser358Trp (c.1073C>G)?

MLYCD p.Ser358Trp (c.1073C>G) is associated with malonic aciduria (ClinVar).

How common is MLYCD p.Ser358Trp (c.1073C>G) in the general population?

MLYCD p.Ser358Trp (c.1073C>G) is ultra-rare (popmax 0.0176%, sas) (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.Ser358Trp (c.1073C>G)?

AlphaMissense predicts likely benign (score 0.1684) — an in-silico prediction, not a clinical call.

MLYCD p.Ser358Trp

c.1073C>G · rs200573073 · VCV848473

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1684 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

malonic aciduria

Computational evidence

Protein change
AlphaMissense	0.1684	likely benign
REVEL	0.253	benign-leaning
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.26	GERP -2.8
Regional constraint	o/e 1.38	unconstrained · MANE · 16 kb · p 1.5e-22 · regional, not allelic
Overall
CADD	15.97	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 0.0176% South Asian · 16/91,080 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00204% 33/1,614,226 alleles · ultra-rare exomes 27/1,461,892 · genomes 6/152,334 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,692
Remaining individualsnot grpmax-eligible	0.016%	6,251
East Asian	0.0134%	7,481
European (non-Finnish)	8.47e-05%	1,180,043

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.Ser358Trp
Coding: c.1073C>G
MANE Select: NM_012213
dbSNP: rs200573073
Type: single nucleotide variant
Location: chr16:83915080 (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 358: 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.Ser358Leu Uncertain significance ★★ ⚠ same residue
MLYCD p.Ser358= Likely benign ★ 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-ser358trp (accessed [today's date]).

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