Is PLTP p.Arg251Gln (c.752G>A) pathogenic?

PLTP p.Arg251Gln (c.752G>A) is classified Uncertain significance in PLTP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-07). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0121%, sas).

How common is PLTP p.Arg251Gln (c.752G>A) in the general population?

PLTP p.Arg251Gln (c.752G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about PLTP p.Arg251Gln (c.752G>A)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

PLTP p.Arg251Gln

c.752G>A · rs367756234 · VCV2277855

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.009	strongly benign-leaning
SaProt	LLR -6.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -6.6	GERP -3.4
Regional constraint	o/e 0.94	unconstrained · MANE · 13 kb · p 0.099 · regional, not allelic
Overall
CADD	3.617	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 0.0121% South Asian · 11/91,088 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00204% 33/1,614,182 alleles · ultra-rare exomes 25/1,461,854 · genomes 8/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,281
African / African-American	0.00799%	12,508
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.00119%	84,287

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.Arg251Gln
Coding: c.752G>A
MANE Select: NM_006227
dbSNP: rs367756234
Type: single nucleotide variant
Location: chr20:45905072 (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.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
PLTP p.Arg432His 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-arg251gln (accessed [today's date]).

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