Is SPEG p.Pro439Arg (c.1316C>G) pathogenic?

SPEG p.Pro439Arg (c.1316C>G) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-11-12). AlphaMissense: likely benign (0.127); Ultra-rare (popmax 0.0232%, mid); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro439Arg (c.1316C>G)?

SPEG p.Pro439Arg (c.1316C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro439Arg (c.1316C>G) in the general population?

SPEG p.Pro439Arg (c.1316C>G) is ultra-rare (popmax 0.0232%, mid) (gnomAD).

What do computational predictors say about SPEG p.Pro439Arg (c.1316C>G)?

AlphaMissense predicts likely benign (score 0.127) — an in-silico prediction, not a clinical call.

SPEG p.Pro439Arg

c.1316C>G · rs1575057382 · VCV1489332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.127	likely benign
REVEL	0.255	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	26.9	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 0.0232% Middle Eastern · 1/4,310 alleles

Filtering AF 8.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000474% 7/1,477,344 alleles · ultra-rare exomes 5/1,325,180 · genomes 2/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0232%	4,310
Admixed American	0.00241%	41,418
Remaining individualsnot grpmax-eligible	0.00175%	56,990
European (non-Finnish)	0.000356%	280,829

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.Pro439Arg
Coding: c.1316C>G
MANE Select: NM_005876
dbSNP: rs1575057382
Type: single nucleotide variant
Location: chr2:219448474 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 439: 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-pro439arg (accessed [today's date]).

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