Is SMPD2 p.Phe162Val (c.484T>G) pathogenic?

SMPD2 p.Phe162Val (c.484T>G) is classified Uncertain significance in SMPD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.6092); Very rare (popmax 8.47e-05%, nfe).

How common is SMPD2 p.Phe162Val (c.484T>G) in the general population?

SMPD2 p.Phe162Val (c.484T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about SMPD2 p.Phe162Val (c.484T>G)?

AlphaMissense predicts likely pathogenic (score 0.6092) — an in-silico prediction, not a clinical call.

SMPD2 p.Phe162Val

c.484T>G · VCV4170700

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6092 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6092	likely pathogenic
REVEL	0.494	indeterminate
SaProt	LLR -11.82	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.25	gain · loss 0.23 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 2,780 bp · p 0.84 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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) · 1/1,180,028 alleles

Overall 6.2e-05% 1/1,614,170 alleles · very rare exomes 1/1,461,884 · genomes 0/152,286 · 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: SMPD2
Protein: p.Phe162Val
Coding: c.484T>G
MANE Select: NM_003080
Type: single nucleotide variant
Location: chr6:109442618 (GRCh38)
Gene constraint: LOEUF 1.046 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.22 · 1 PDB
Residue 162: an α-helix

Full SMPD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SMPD2 p.Phe162Cys Uncertain significance ★ ⚠ same residue
SMPD2 p.Ala132Thr Uncertain significance ★ ⚠ same type
SMPD2 p.Ala200Thr Uncertain significance ★ ⚠ same type
SMPD2 p.Ala309Thr Uncertain significance ★ ⚠ same type
SMPD2 p.Ala327Thr Uncertain significance ★ ⚠ same type
SMPD2 p.Ala327Val Uncertain significance ★ ⚠ same type
SMPD2 p.Ala368Val Uncertain significance ★ ⚠ same type
SMPD2 p.Ala370Thr 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/smpd2-p-phe162val (accessed [today's date]).

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