Is PLTP p.Pro409Thr (c.1225C>A) pathogenic?

PLTP p.Pro409Thr (c.1225C>A) is classified Uncertain significance in PLTP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.2895); Very rare (popmax 0.00401%, afr).

How common is PLTP p.Pro409Thr (c.1225C>A) in the general population?

PLTP p.Pro409Thr (c.1225C>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about PLTP p.Pro409Thr (c.1225C>A)?

AlphaMissense predicts likely benign (score 0.2895) — an in-silico prediction, not a clinical call.

PLTP p.Pro409Thr

c.1225C>A · rs1455944943 · VCV2531913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2895	likely benign
REVEL	0.182	moderately benign-leaning
SaProt	LLR -11.10	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 13 kb · p 0.099 · regional, not allelic
Overall
CADD	25.7	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 0.00401% African / African-American · 3/74,898 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,614,048 alleles · very rare exomes 2/1,461,886 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,966
Admixed American	0.00167%	59,996

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.Pro409Thr
Coding: c.1225C>A
MANE Select: NM_006227
dbSNP: rs1455944943
Type: single nucleotide variant
Location: chr20:45899679 (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-pro409thr (accessed [today's date]).

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