Is IGSF1 p.Pro228Arg (c.683C>G) pathogenic?

IGSF1 p.Pro228Arg (c.683C>G) is classified Uncertain significance in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-26). AlphaMissense: likely pathogenic (0.9777); Absent from gnomAD v4.1.

How common is IGSF1 p.Pro228Arg (c.683C>G) in the general population?

IGSF1 p.Pro228Arg (c.683C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IGSF1 p.Pro228Arg (c.683C>G)?

AlphaMissense predicts likely pathogenic (score 0.9777) — an in-silico prediction, not a clinical call.

IGSF1 p.Pro228Arg

c.683C>G · rs2522265115 · VCV1806552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9777 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9777	likely pathogenic · top 2% in IGSF1
REVEL	0.284	benign-leaning
SaProt	LLR -15.81	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 7,945 bp · p 0.77 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IGSF1
Protein: p.Pro228Arg
Coding: c.683C>G
MANE Select: NM_001555
dbSNP: rs2522265115
Type: single nucleotide variant
Location: chrX:131283249 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 228: the ig-like c2-type 3 domain

Full IGSF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGSF1 p.Pro228Leu Uncertain significance ★ ⚠ same residue
IGSF1 p.Arg1184Ter Pathogenic ★★ same type
IGSF1 p.Asp853Gly Uncertain significance ★★ ⚠ same type
IGSF1 p.Ile1221Thr Uncertain significance ★★ ⚠ same type
IGSF1 p.Thr1302Ile Uncertain significance ★★ ⚠ same type
IGSF1 p.Thr1316Ile Uncertain significance ★★ ⚠ same type
IGSF1 c.2041+24G>A Benign ★★ same type
IGSF1 c.2042-70G>C Benign ★★ 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/igsf1-p-pro228arg (accessed [today's date]).

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