Is PLOD3 p.Ser346Phe (c.1037C>T) pathogenic?

PLOD3 p.Ser346Phe (c.1037C>T) is classified Likely benign in PLOD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1086); Rare (popmax 0.109%, sas).

How common is PLOD3 p.Ser346Phe (c.1037C>T) in the general population?

PLOD3 p.Ser346Phe (c.1037C>T) is rare (popmax 0.109%, sas) (gnomAD).

What do computational predictors say about PLOD3 p.Ser346Phe (c.1037C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

PLOD3 p.Ser346Phe

c.1037C>T · rs150001477 · VCV1589417

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.308	indeterminate
SaProt	LLR -5.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.038, phastCons 0.002
Regional constraint	o/e 1.06	unconstrained · MANE · 6,691 bp · p 0.12 · regional, not allelic
Overall
CADD	5.971	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 0.109% South Asian · 99/91,072 alleles

Filtering AF 0.0914% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0849%

Overall 0.0483% 779/1,613,908 alleles · rare exomes 725/1,461,640 · genomes 54/152,268 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.109%	920
Remaining individualsnot grpmax-eligible	0.056%	1,785
European (non-Finnish)	0.0514%	1,947
African / African-American	0.0333%	3,001
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289
Admixed American	0.00667%	15,004
East Asian	0.00223%	44,876

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.Ser346Phe
Coding: c.1037C>T
MANE Select: NM_001084
dbSNP: rs150001477
Type: single nucleotide variant
Location: chr7:101212343 (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 346: the 'accessory region' region; an α-helix

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

Similar variants

PLOD3 p.Ser346fs Pathogenic ★ same residue
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

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-ser346phe (accessed [today's date]).

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