Is MLYCD p.Ser290Phe (c.869C>T) pathogenic?

MLYCD p.Ser290Phe (c.869C>T) is classified Uncertain significance in MLYCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-06). AlphaMissense: likely pathogenic (0.9858); Very rare (popmax 0.00167%, amr); Associated with malonic aciduria.

What condition is associated with MLYCD p.Ser290Phe (c.869C>T)?

MLYCD p.Ser290Phe (c.869C>T) is associated with malonic aciduria (ClinVar).

How common is MLYCD p.Ser290Phe (c.869C>T) in the general population?

MLYCD p.Ser290Phe (c.869C>T) is very rare (popmax 0.00167%, amr) (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.Ser290Phe (c.869C>T)?

AlphaMissense predicts likely pathogenic (score 0.9858) — an in-silico prediction, not a clinical call.

MLYCD p.Ser290Phe

c.869C>T · rs997003558 · VCV2137850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9858 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

malonic aciduria

Computational evidence

Protein change
AlphaMissense	0.9858	likely pathogenic · top 3% in MLYCD
REVEL	0.859	moderately pathogenic-leaning
SaProt	LLR -11.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 16 kb · p 1.5e-22 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,090 alleles · very rare exomes 2/1,461,878 · genomes 1/152,212 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,014
European (non-Finnish)	0.000169%	590,023

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.Ser290Phe
Coding: c.869C>T
MANE Select: NM_012213
dbSNP: rs997003558
Type: single nucleotide variant
Location: chr16:83912288 (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 290: the 'catalytic domain' region; a β-strand

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.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
MLYCD p.Arg392Gln Uncertain significance ★★ ⚠ same condition
MLYCD p.Arg392Trp 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-ser290phe (accessed [today's date]).

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