Is POMP p.Leu67Val (c.199C>G) pathogenic?

POMP p.Leu67Val (c.199C>G) is classified Uncertain significance in POMP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-06). AlphaMissense: likely benign (0.2148); Very rare (popmax 8.48e-05%, nfe).

How common is POMP p.Leu67Val (c.199C>G) in the general population?

POMP p.Leu67Val (c.199C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about POMP p.Leu67Val (c.199C>G)?

AlphaMissense predicts likely benign (score 0.2148) — an in-silico prediction, not a clinical call.

POMP p.Leu67Val

c.199C>G · VCV4730672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2148 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2148	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -9.67	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 1.4	GERP 0.027, phastCons 0.8
Regional constraint	o/e 0.84	unconstrained · MANE · 19 kb · p 0.048 · regional, not allelic
Overall
CADD	21.4	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 8.48e-05% European (non-Finnish) · 1/1,178,622 alleles

Overall 6.2e-05% 1/1,612,520 alleles · very rare exomes 1/1,460,226 · genomes 0/152,294 · 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: POMP
Protein: p.Leu67Val
Coding: c.199C>G
MANE Select: NM_015932
Type: single nucleotide variant
Location: chr13:28668509 (GRCh38)
Gene constraint: LOEUF 1.191 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 81.76 · 11 PDB
Residue 67: an α-helix

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

Similar variants

POMP p.Leu67Pro Uncertain significance ★ ⚠ same residue
POMP p.Arg32Gln Uncertain significance ★★ ⚠ same type
POMP p.Arg32Trp Uncertain significance ★★ ⚠ same type
POMP p.Asn108His Uncertain significance ★★ ⚠ same type
POMP p.Asn40Ser Uncertain significance ★★ ⚠ same type
POMP p.Gln56His Uncertain significance ★★ ⚠ same type
POMP p.His28Pro Uncertain significance ★★ ⚠ same type
POMP p.Ile112Val 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/pomp-p-leu67val (accessed [today's date]).

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