Is IGSF1 p.Pro419= (c.1257C>G) pathogenic?

IGSF1 p.Pro419= (c.1257C>G) is classified Likely benign in IGSF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-11). Very rare (popmax 0.00218%, amr).

How common is IGSF1 p.Pro419= (c.1257C>G) in the general population?

IGSF1 p.Pro419= (c.1257C>G) is very rare (popmax 0.00218%, amr) (gnomAD).

IGSF1 p.Pro419=

c.1257C>G · VCV4952860

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -4.8, phastCons 0.95
Overall
CADD	6.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00218% Admixed American · 1/45,776 alleles

Overall 0.000166% 2/1,203,872 alleles · very rare exomes 2/1,090,852 · genomes 0/113,020 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00218%	45,776
Remaining individualsnot grpmax-eligible	0.00211%	47,324

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: IGSF1
Protein: p.Pro419=
Coding: c.1257C>G
MANE Select: NM_001555
Type: single nucleotide variant
Location: chrX:131281934 (GRCh38)
Structure: AlphaFold pLDDT 73.64
Residue 419: the ig-like c2-type 5 domain

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

Similar variants

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
IGSF1 c.2896+34G>A 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-pro419 (accessed [today's date]).

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