Is PLTP p.Val448Ala (c.1343T>C) pathogenic?

PLTP p.Val448Ala (c.1343T>C) is classified Uncertain significance in PLTP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-21). AlphaMissense: likely benign (0.1147); Very rare (popmax 0.00492%, nfe).

How common is PLTP p.Val448Ala (c.1343T>C) in the general population?

PLTP p.Val448Ala (c.1343T>C) is very rare (popmax 0.00492%, nfe) (gnomAD).

What do computational predictors say about PLTP p.Val448Ala (c.1343T>C)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

PLTP p.Val448Ala

c.1343T>C · rs766917794 · VCV2181717

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00492%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.2	benign-leaning
SaProt	LLR -7.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 0.94, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 13 kb · p 0.099 · regional, not allelic
Overall
CADD	21.2	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 0.00492% European (non-Finnish) · 58/1,179,968 alleles

Filtering AF 0.00386% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00353%

Overall 0.00417% 61/1,461,878 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00492%	20,344
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Val448Ala
Coding: c.1343T>C
MANE Select: NM_006227
dbSNP: rs766917794
Type: single nucleotide variant
Location: chr20:45899478 (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.Val448= Benign ★ same residue
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

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-val448ala (accessed [today's date]).

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