Is PLOD2 p.Cys4Ser (c.10T>A) pathogenic?

PLOD2 p.Cys4Ser (c.10T>A) is classified Benign/Likely benign in PLOD2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.079); Low-frequency (popmax 2.34%, afr); Associated with Bruck syndrome 2.

What condition is associated with PLOD2 p.Cys4Ser (c.10T>A)?

PLOD2 p.Cys4Ser (c.10T>A) is associated with Bruck syndrome 2 (ClinVar).

How common is PLOD2 p.Cys4Ser (c.10T>A) in the general population?

PLOD2 p.Cys4Ser (c.10T>A) is low-frequency (popmax 2.34%, afr) (gnomAD).

What do computational predictors say about PLOD2 p.Cys4Ser (c.10T>A)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

PLOD2 p.Cys4Ser

c.10T>A · rs116803293 · VCV717837

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.34%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bruck syndrome 2

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -5.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -3.3
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	0.97	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 2.34% African / African-American · 1,738/74,330 alleles

Filtering AF 2.25% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.21%

Overall 0.12% 1,901/1,580,650 alleles · low-frequency exomes 913/1,428,420 · genomes 988/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.34%	43
Remaining individualsnot grpmax-eligible	0.136%	737
Admixed American	0.116%	863
Middle Eastern	0.0513%	1,951
European (non-Finnish)	0.00103%	96,913

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: PLOD2
Protein: p.Cys4Ser
Coding: c.10T>A
MANE Select: NM_182943
dbSNP: rs116803293
Type: single nucleotide variant
Location: chr3:146160980 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63

Full PLOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Bruck syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLOD2 p.Cys4fs Pathogenic/Likely pathogenic ★★ same residue
PLOD2 p.Arg440Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 p.Arg680Ter Pathogenic/Likely pathogenic ★★ same condition
PLOD2 c.-170C>G Uncertain significance ★★ same condition
PLOD2 p.Ala415Val Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg619Cys Uncertain significance ★★ ⚠ same condition
PLOD2 p.Arg648Trp 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/plod2-p-cys4ser (accessed [today's date]).

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