Is SPEG p.Ser320Phe (c.959C>T) pathogenic?

SPEG p.Ser320Phe (c.959C>T) is classified Uncertain significance in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.3398); Very rare (popmax 0.00508%, amr); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Ser320Phe (c.959C>T)?

SPEG p.Ser320Phe (c.959C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Ser320Phe (c.959C>T) in the general population?

SPEG p.Ser320Phe (c.959C>T) is very rare (popmax 0.00508%, amr) (gnomAD).

What do computational predictors say about SPEG p.Ser320Phe (c.959C>T)?

AlphaMissense predicts likely benign (score 0.3398) — an in-silico prediction, not a clinical call.

SPEG p.Ser320Phe

c.959C>T · VCV4173409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3398	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	22.8	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00508% Admixed American · 3/59,000 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000674%

Overall 0.000276% 4/1,450,746 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00508%	19,667
European (non-Finnish)	8.51e-05%	1,175,004

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: SPEG
Protein: p.Ser320Phe
Coding: c.959C>T
MANE Select: NM_005876
Type: single nucleotide variant
Location: chr2:219448117 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 320: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1334Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1628Val Uncertain significance ★★ same condition
SPEG p.Ala1686Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala199Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala220Ser Uncertain significance ★★ ⚠ same condition
SPEG p.Ala241Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala291Gly Uncertain significance ★★ ⚠ same condition

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/speg-p-ser320phe (accessed [today's date]).

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