Is PLOD3 p.Arg235Trp (c.703C>T) pathogenic?

PLOD3 p.Arg235Trp (c.703C>T) is classified Uncertain significance in PLOD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-25). AlphaMissense: likely benign (0.1506); Ultra-rare (popmax 0.0999%, sas).

How common is PLOD3 p.Arg235Trp (c.703C>T) in the general population?

PLOD3 p.Arg235Trp (c.703C>T) is ultra-rare (popmax 0.0999%, sas) (gnomAD).

What do computational predictors say about PLOD3 p.Arg235Trp (c.703C>T)?

AlphaMissense predicts likely benign (score 0.1506) — an in-silico prediction, not a clinical call.

PLOD3 p.Arg235Trp

c.703C>T · rs146134980 · VCV1523116

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1506 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0999%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1506	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -9.78	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 7.4	GERP 0.78, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,691 bp · p 0.12 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0999% South Asian · 91/91,058 alleles

Filtering AF 0.0833% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0771%

Overall 0.0175% 282/1,613,242 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0999%	1,001
Middle Eastern	0.0825%	1,212
African / African-American	0.08%	1,250
Admixed American	0.0233%	4,285
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)	0.00865%	11,561
East Asian	0.00223%	44,866

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: PLOD3
Protein: p.Arg235Trp
Coding: c.703C>T
MANE Select: NM_001084
dbSNP: rs146134980
Type: single nucleotide variant
Location: chr7:101213181 (GRCh38)
Gene constraint: LOEUF 0.925 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 18 PDB
Residue 235: the 'required for glycosyltransferase activity' region

Full PLOD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLOD3 c.1359-1G>C Likely pathogenic ★★ same type
PLOD3 p.Arg452Ter Pathogenic ★★ same type
PLOD3 p.Tyr630Ter Pathogenic/Likely pathogenic ★★ same type
PLOD3 c.338+6G>C Uncertain significance ★★ same type
PLOD3 p.Ala371Val Uncertain significance ★★ ⚠ same type
PLOD3 p.Ala431Thr Uncertain significance ★★ ⚠ same type
PLOD3 p.Ala59Val Uncertain significance ★★ ⚠ same type
PLOD3 p.Ala646Val 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/plod3-p-arg235trp (accessed [today's date]).

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