Is IGSF10 p.His135Pro (c.404A>C) pathogenic?

IGSF10 p.His135Pro (c.404A>C) is classified Uncertain significance in IGSF10 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-27). AlphaMissense: likely pathogenic (0.9472); Ultra-rare (popmax 0.0138%, nfe).

How common is IGSF10 p.His135Pro (c.404A>C) in the general population?

IGSF10 p.His135Pro (c.404A>C) is ultra-rare (popmax 0.0138%, nfe) (gnomAD).

What do computational predictors say about IGSF10 p.His135Pro (c.404A>C)?

AlphaMissense predicts likely pathogenic (score 0.9472) — an in-silico prediction, not a clinical call.

IGSF10 p.His135Pro

c.404A>C · rs143943953 · VCV1960784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9472 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9472	likely pathogenic · top 3% in IGSF10
REVEL	0.522	indeterminate
SaProt	LLR -11.44	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.0097 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0138% European (non-Finnish) · 163/1,178,184 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0107% 173/1,611,802 alleles · ultra-rare exomes 165/1,459,608 · genomes 8/152,194 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0138%	7,228
Remaining individualsnot grpmax-eligible	0.0128%	7,802
African / African-American	0.00267%	37,436

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.His135Pro
Coding: c.404A>C
MANE Select: NM_178822
dbSNP: rs143943953
Type: single nucleotide variant
Location: chr3:151453695 (GRCh38)
Gene constraint: LOEUF 1.068 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.70

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

Similar variants

IGSF10 p.Ala1666Gly Uncertain significance ★★ ⚠ same type
IGSF10 p.Ala1725Thr Uncertain significance ★★ ⚠ same type
IGSF10 p.Ala275Thr Uncertain significance ★★ ⚠ same type
IGSF10 p.Arg1484Thr Uncertain significance ★★ ⚠ same type
IGSF10 p.Arg1684Thr Uncertain significance ★★ ⚠ same type
IGSF10 p.Arg2403Gln Uncertain significance ★★ ⚠ same type
IGSF10 p.Arg2410His Uncertain significance ★★ ⚠ same type
IGSF10 p.Arg2529Gln 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/igsf10-p-his135pro (accessed [today's date]).

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