Is MLYCD c.641+3A>C pathogenic?

MLYCD c.641+3A>C is classified Uncertain significance in MLYCD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). Ultra-rare (popmax 0.0183%, nfe); Associated with malonic aciduria.

What condition is associated with MLYCD c.641+3A>C?

MLYCD c.641+3A>C is associated with malonic aciduria (ClinVar).

How common is MLYCD c.641+3A>C in the general population?

MLYCD c.641+3A>C is ultra-rare (popmax 0.0183%, nfe) (gnomAD).

How is Malonic aciduria inherited?

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

MLYCD c.641+3A>C

rs370078811 · VCV577880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, nfe)

Conditions

malonic aciduria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	Δ0.46	donor loss · deltas
Pangolin	Δ0.75	loss · gain 0.67 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.04	GERP -3, phastCons 0.017
Non-coding constraint	Z -1.32	1 kb window · o/e 1.12 · regional · uncalibrated
Overall
CADD	7.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0183% European (non-Finnish) · 215/1,172,406 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0155%

Overall 0.0144% 232/1,605,712 alleles · ultra-rare exomes 219/1,453,490 · genomes 13/152,222 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0183%	5,453
Remaining individualsnot grpmax-eligible	0.0113%	8,887
Finnishnot grpmax-eligible	0.00937%	10,671
African / African-American	0.00401%	24,921
East Asian	0.00223%	44,858

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
Coding: c.641+3A>C
MANE Select: NM_012213
dbSNP: rs370078811
Type: single nucleotide variant
Location: chr16:83907102 (GRCh38)
Gene constraint: LOEUF 1.165 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.16 · 2 PDB

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-c-641-plus-3a-c (accessed [today's date]).

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