Is RIN2 p.His606= (c.1818C>T) pathogenic?

RIN2 p.His606= (c.1818C>T) is classified Benign in RIN2 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-04). Common (popmax 73.9%, eas) — too common for a highly-penetrant pathogenic allele; Associated with RIN2 syndrome.

What condition is associated with RIN2 p.His606= (c.1818C>T)?

RIN2 p.His606= (c.1818C>T) is associated with RIN2 syndrome (ClinVar).

RIN2 p.His606=

Q: How common is RIN2 p.His606= (c.1818C>T) in the general population?

RIN2 p.His606= (c.1818C>T) is common (popmax 73.9%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1818C>T · rs2076584 · VCV257654

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Common

common (popmax 73.9%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

RIN2 syndrome

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 -3.6	GERP -4
Overall
CADD	7.007	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 73.9% East Asian · 32,719/44,258 alleles

Filtering AF 73.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 73%

Overall 32.8% 523,551/1,596,974 alleles · common exomes 469,719/1,444,848 · genomes 53,832/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	73.9%	1
Admixed American	55%	2
African / African-American	38.5%	3
Remaining individualsnot grpmax-eligible	34.1%	3
Ashkenazi Jewishnot grpmax-eligible	34%	3
European (non-Finnish)	30.8%	3
Amishnot grpmax-eligible	28.4%	4
Middle Eastern	25.9%	4
South Asian	24.7%	4
Finnishnot grpmax-eligible	24%	4

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: RIN2
Protein: p.His606=
Coding: c.1818C>T
MANE Select: NM_018993
dbSNP: rs2076584
Type: single nucleotide variant
Location: chr20:19990061 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30

Full RIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RIN2 syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIN2 p.Asn266Ile Uncertain significance ★★ ⚠ same condition
RIN2 p.His340Arg Uncertain significance ★★ ⚠ same condition
RIN2 p.Pro308Ala Uncertain significance ★★ ⚠ same condition
RIN2 p.Pro308Gln Uncertain significance ★★ ⚠ same condition
RIN2 p.Ser800Cys Uncertain significance ★★ ⚠ same condition
RIN2 p.Val840Ile Uncertain significance ★★ ⚠ same condition
RIN2 c.159-17G>A Likely benign ★★ same condition
RIN2 c.2201-47G>A Benign ★★ same condition

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/rin2-p-his606 (accessed [today's date]).

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