Is SPEG p.Arg116Pro (c.347G>C) pathogenic?

SPEG p.Arg116Pro (c.347G>C) is classified Uncertain significance in SPEG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-10). AlphaMissense: likely pathogenic (0.5973); Ultra-rare (popmax 0.0135%, amr).

How common is SPEG p.Arg116Pro (c.347G>C) in the general population?

SPEG p.Arg116Pro (c.347G>C) is ultra-rare (popmax 0.0135%, amr) (gnomAD).

What do computational predictors say about SPEG p.Arg116Pro (c.347G>C)?

AlphaMissense predicts likely pathogenic (score 0.5973) — an in-silico prediction, not a clinical call.

SPEG p.Arg116Pro

c.347G>C · rs756522056 · VCV1418818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.5973	likely pathogenic
REVEL	0.243	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP -2.8, phastCons 0.93
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	19.48	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0135% Admixed American · 7/51,770 alleles

Filtering AF 0.0063% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0045%

Overall 0.00052% 8/1,537,484 alleles · ultra-rare exomes 7/1,385,258 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0135%	7,396
South Asian	0.00118%	84,764

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.Arg116Pro
Coding: c.347G>C
MANE Select: NM_005876
dbSNP: rs756522056
Type: single nucleotide variant
Location: chr2:219435324 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 116: the ig-like 1 domain

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

Similar variants

SPEG p.Arg116Trp Uncertain significance ★ ⚠ same residue
SPEG p.Arg1467Ter Likely pathogenic ★★ same type
SPEG p.Ser131Ter Pathogenic/Likely pathogenic ★★ same type
SPEG c.3301+5G>A Uncertain significance ★★ same type
SPEG c.478+5G>A Uncertain significance ★★ same type
SPEG p.Ala121Thr Uncertain significance ★★ same type
SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same type
SPEG p.Ala1334Val 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/speg-p-arg116pro (accessed [today's date]).

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