Is MLYCD p.Arg455Cys (c.1363C>T) pathogenic?

MLYCD p.Arg455Cys (c.1363C>T) is classified Uncertain significance in MLYCD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-18). AlphaMissense: likely benign (0.2483); Ultra-rare (popmax 0.02%, eas); Associated with Inborn genetic diseases.

What condition is associated with MLYCD p.Arg455Cys (c.1363C>T)?

MLYCD p.Arg455Cys (c.1363C>T) is associated with Inborn genetic diseases, malonic aciduria (ClinVar).

How common is MLYCD p.Arg455Cys (c.1363C>T) in the general population?

MLYCD p.Arg455Cys (c.1363C>T) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about MLYCD p.Arg455Cys (c.1363C>T)?

AlphaMissense predicts likely benign (score 0.2483) — an in-silico prediction, not a clinical call.

MLYCD p.Arg455Cys

c.1363C>T · rs778179498 · VCV2193241

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2483	likely benign
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -13.62	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 16 kb · p 1.5e-22 · regional, not allelic
Overall
CADD	29.8	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 0.02% East Asian · 9/44,888 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00118% 19/1,613,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.02%	4,988
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,243
Admixed American	0.00167%	60,006
European (non-Finnish)	0.000508%	196,675

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.Arg455Cys
Coding: c.1363C>T
MANE Select: NM_012213
dbSNP: rs778179498
Type: single nucleotide variant
Location: chr16:83915370 (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 455: the 'catalytic domain' region; a β-strand

Full MLYCD 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: malonic aciduria

Similar variants

MLYCD p.Arg455Leu Uncertain significance ★ ⚠ same residue
MLYCD p.Arg455= Likely benign ★ same residue
MLYCD p.Arg455His Uncertain significance ★ ⚠ 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

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-arg455cys (accessed [today's date]).

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