Is IGSF10 p.Ser2000fs (c.5996dup) pathogenic?

IGSF10 p.Ser2000fs (c.5996dup) is classified Likely benign in IGSF10 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). Very rare (popmax 0.00966%, nfe).

How common is IGSF10 p.Ser2000fs (c.5996dup) in the general population?

IGSF10 p.Ser2000fs (c.5996dup) is very rare (popmax 0.00966%, nfe) (gnomAD).

IGSF10 p.Ser2000fs

c.5996dup · rs770294032 · VCV2917716

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00966%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (8 of 8) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.4	GERP -4, phastCons 0.001
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00966% European (non-Finnish) · 114/1,179,984 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00761%

Overall 0.0154% 248/1,613,544 alleles · very rare exomes 224/1,461,458 · genomes 24/152,086 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.402%	249
Remaining individualsnot grpmax-eligible	0.0208%	4,806
European (non-Finnish)grpmax	0.00966%	10,351
Finnishnot grpmax-eligible	0.00314%	31,841

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: IGSF10
Protein: p.Ser2000fs
Coding: c.5996dup
MANE Select: NM_178822
dbSNP: rs770294032
Type: Duplication
Location: chr3:151438564 (GRCh38)
Gene constraint: LOEUF 1.068 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.70
Residue 2000: the ig-like c2-type 6 domain

Full IGSF10 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IGSF10 p.Leu2452fs Likely benign ★★ same type
IGSF10 p.Thr2518fs Benign ★★ same type
IGSF10 p.Ala1160fs Uncertain significance ★ same type
IGSF10 p.Ile2445_Ser2446insIle Uncertain significance ★ same type
IGSF10 p.Leu429fs Uncertain significance ★ same type
IGSF10 p.Ser2268_Pro2269insSer Uncertain significance ★ same type
IGSF10 p.Val2524fs Uncertain significance ★ same type
IGSF10 c.5964-17dup 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/igsf10-p-ser2000fs (accessed [today's date]).

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