Is MLYCD p.Ser491Ile (c.1472G>T) pathogenic?

MLYCD p.Ser491Ile (c.1472G>T) is classified Uncertain significance in MLYCD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.7211); Ultra-rare (popmax 0.0604%, sas); Associated with Inborn genetic diseases.

What condition is associated with MLYCD p.Ser491Ile (c.1472G>T)?

MLYCD p.Ser491Ile (c.1472G>T) is associated with Inborn genetic diseases, malonic aciduria (ClinVar).

How common is MLYCD p.Ser491Ile (c.1472G>T) in the general population?

MLYCD p.Ser491Ile (c.1472G>T) is ultra-rare (popmax 0.0604%, sas) (gnomAD).

What do computational predictors say about MLYCD p.Ser491Ile (c.1472G>T)?

AlphaMissense predicts likely pathogenic (score 0.7211) — an in-silico prediction, not a clinical call.

MLYCD p.Ser491Ile

c.1472G>T · rs751002859 · VCV886367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7211 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0604%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7211	likely pathogenic
REVEL	0.648	pathogenic-leaning
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.38	unconstrained · MANE · 16 kb · p 1.5e-22 · regional, not allelic
Overall
CADD	27.7	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 0.0604% South Asian · 55/91,090 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.043%

Overall 0.00577% 93/1,611,444 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0604%	1,656
Remaining individualsnot grpmax-eligible	0.0064%	15,615
European (non-Finnish)	0.00288%	34,706

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.Ser491Ile
Coding: c.1472G>T
MANE Select: NM_012213
dbSNP: rs751002859
Type: single nucleotide variant
Location: chr16:83915479 (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 491: the 'catalytic domain' region

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.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-ser491ile (accessed [today's date]).

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