Is LIPC p.Ser249Phe (c.746C>T) pathogenic?

LIPC p.Ser249Phe (c.746C>T) is classified Uncertain significance in LIPC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely benign (0.1895); Very rare (popmax 8.47e-05%, nfe).

How common is LIPC p.Ser249Phe (c.746C>T) in the general population?

LIPC p.Ser249Phe (c.746C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about LIPC p.Ser249Phe (c.746C>T)?

AlphaMissense predicts likely benign (score 0.1895) — an in-silico prediction, not a clinical call.

LIPC p.Ser249Phe

c.746C>T · rs2548785781 · VCV2532104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1895 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1895	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3	GERP 3.8, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 137 kb · p 0.056 · regional, not allelic
Overall
CADD	22.0	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 8.47e-05% European (non-Finnish) · 1/1,180,042 alleles

Overall 6.19e-05% 1/1,614,214 alleles · very rare exomes 1/1,461,888 · genomes 0/152,326 · joint denominator

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: LIPC
Protein: p.Ser249Phe
Coding: c.746C>T
MANE Select: NM_000236
dbSNP: rs2548785781
Type: single nucleotide variant
Location: chr15:58545913 (GRCh38)
Gene constraint: LOEUF 1.102 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.03

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

Similar variants

LIPC c.456+2T>C Uncertain significance ★★ same type
LIPC c.456+5C>T Uncertain significance ★★ same type
LIPC p.Ala105Val Uncertain significance ★★ ⚠ same type
LIPC p.Ala106Val Uncertain significance ★★ ⚠ same type
LIPC p.Arg135Cys Uncertain significance ★★ ⚠ same type
LIPC p.Arg135His Uncertain significance ★★ ⚠ same type
LIPC p.Arg138Cys Uncertain significance ★★ ⚠ same type
LIPC p.Arg225Gln 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/lipc-p-ser249phe (accessed [today's date]).

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