Is MLYCD p.Ser477Cys (c.1430C>G) pathogenic?

MLYCD p.Ser477Cys (c.1430C>G) is classified Uncertain significance in MLYCD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). AlphaMissense: ambiguous (0.4314); Very rare (popmax 0.00119%, nfe).

How common is MLYCD p.Ser477Cys (c.1430C>G) in the general population?

MLYCD p.Ser477Cys (c.1430C>G) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about MLYCD p.Ser477Cys (c.1430C>G)?

AlphaMissense predicts ambiguous (score 0.4314) — an in-silico prediction, not a clinical call.

MLYCD p.Ser477Cys

c.1430C>G · VCV4931587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4314 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4314	ambiguous
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -12.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.30	donor gain · deltas
Pangolin	Δ0.43	gain · loss 0.00 · agrees with SpliceAI · independent
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	31.0	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 0.00119% European (non-Finnish) · 14/1,180,052 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00105% 17/1,613,528 alleles · very rare exomes 16/1,461,266 · genomes 1/152,262 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00158%	63,432
European (non-Finnish)grpmax	0.00119%	84,289

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser477Cys
Coding: c.1430C>G
MANE Select: NM_012213
Type: single nucleotide variant
Location: chr16:83915437 (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 477: the 'catalytic domain' region

Full MLYCD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MLYCD p.Ser477= Likely benign ★ same residue
MLYCD p.Ser187Ter Pathogenic ★★ same type
MLYCD c.*218C>A Uncertain significance ★★ same type
MLYCD p.Ala119Ser Uncertain significance ★★ ⚠ same type
MLYCD p.Ala415Thr Uncertain significance ★★ ⚠ same type
MLYCD p.Arg199Gln Uncertain significance ★★ ⚠ same type
MLYCD p.Arg235Gly Uncertain significance ★★ ⚠ same type
MLYCD p.Arg392Gln Uncertain significance ★★ ⚠ same type

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-ser477cys (accessed [today's date]).

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