Is INSRR p.Pro628Arg (c.1883C>G) pathogenic?

INSRR p.Pro628Arg (c.1883C>G) is classified Uncertain significance in INSRR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-18). AlphaMissense: likely pathogenic (0.9867); Ultra-rare (popmax 0.0217%, amr).

How common is INSRR p.Pro628Arg (c.1883C>G) in the general population?

INSRR p.Pro628Arg (c.1883C>G) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about INSRR p.Pro628Arg (c.1883C>G)?

AlphaMissense predicts likely pathogenic (score 0.9867) — an in-silico prediction, not a clinical call.

INSRR p.Pro628Arg

c.1883C>G · rs780030769 · VCV2354542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9867 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9867	likely pathogenic · top 7% in INSRR
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -18.67	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 18 kb · p 0.06 · regional, not allelic
Overall
CADD	26.2	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 0.0217% Admixed American · 13/59,816 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00093% 15/1,613,228 alleles · ultra-rare exomes 14/1,461,120 · genomes 1/152,108 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,601
Remaining individualsnot grpmax-eligible	0.0016%	62,446
African / African-American	0.00134%	74,856

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: INSRR
Protein: p.Pro628Arg
Coding: c.1883C>G
MANE Select: NM_014215
dbSNP: rs780030769
Type: single nucleotide variant
Location: chr1:156846047 (GRCh38)
Gene constraint: LOEUF 1.013 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.47 · 4 PDB
Residue 628: the fibronectin type-iii 2 domain

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

Similar variants

INSRR p.Arg136Cys Uncertain significance ★★ ⚠ same type
INSRR p.Ile1131Asn Uncertain significance ★★ ⚠ same type
NTRK1 p.Ala40Glu Uncertain significance ★★ ⚠ same type
INSRR c.1811-5C>T Benign ★★ same type
INSRR p.Arg279Cys Likely benign ★★ ⚠ same type
INSRR p.Arg554Cys Likely benign ★★ ⚠ same type
INSRR p.Cys246Arg Likely benign ★★ same type
INSRR p.Gln763= 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/insrr-p-pro628arg (accessed [today's date]).

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