Is PLTP p.Ser345Phe (c.1034C>T) pathogenic?

PLTP p.Ser345Phe (c.1034C>T) is classified Uncertain significance in PLTP (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-26). AlphaMissense: likely benign (0.1709); Very rare (popmax 0.00305%, nfe).

How common is PLTP p.Ser345Phe (c.1034C>T) in the general population?

PLTP p.Ser345Phe (c.1034C>T) is very rare (popmax 0.00305%, nfe) (gnomAD).

What do computational predictors say about PLTP p.Ser345Phe (c.1034C>T)?

AlphaMissense predicts likely benign (score 0.1709) — an in-silico prediction, not a clinical call.

PLTP p.Ser345Phe

c.1034C>T · rs377317376 · VCV2470439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00305%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1709	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -7.78	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 7.5	GERP 0.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 13 kb · p 0.099 · regional, not allelic
Overall
CADD	22.3	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 0.00305% European (non-Finnish) · 36/1,179,994 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00242% 39/1,614,082 alleles · very rare exomes 35/1,461,818 · genomes 4/152,264 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00468%	21,347
European (non-Finnish)grpmax	0.00305%	32,778

Finnish 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: PLTP
Protein: p.Ser345Phe
Coding: c.1034C>T
MANE Select: NM_006227
dbSNP: rs377317376
Type: single nucleotide variant
Location: chr20:45902513 (GRCh38)
Gene constraint: LOEUF 1.002 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.36

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

Similar variants

PLTP p.Ala155Thr Uncertain significance ★★ ⚠ same type
PLTP p.Ala155Val Uncertain significance ★★ ⚠ same type
PLTP p.Arg177Cys Uncertain significance ★★ ⚠ same type
PLTP p.Arg251Gln Uncertain significance ★★ ⚠ same type
PLTP p.Arg372His Uncertain significance ★★ ⚠ same type
PLTP p.Arg380Gln Uncertain significance ★★ ⚠ same type
PLTP p.Arg391Cys Uncertain significance ★★ ⚠ same type
PLTP p.Arg394Pro 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/pltp-p-ser345phe (accessed [today's date]).

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