Is CHN1 p.Val65Met (c.193G>A) pathogenic?

CHN1 p.Val65Met (c.193G>A) is classified Uncertain significance in CHN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-28). AlphaMissense: likely benign (0.0865); Very rare (popmax 0.00267%, afr); Associated with Duane retraction syndrome 2.

What condition is associated with CHN1 p.Val65Met (c.193G>A)?

CHN1 p.Val65Met (c.193G>A) is associated with Duane retraction syndrome 2 (ClinVar).

How common is CHN1 p.Val65Met (c.193G>A) in the general population?

CHN1 p.Val65Met (c.193G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CHN1 p.Val65Met (c.193G>A)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

CHN1 p.Val65Met

c.193G>A · rs370140469 · VCV892784

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Duane retraction syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 127 kb · p 0.27 · regional, not allelic
Overall
CADD	19.42	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00267% African / African-American · 2/74,908 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,262 alleles · very rare

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: CHN1
Protein: p.Val65Met
Coding: c.193G>A
MANE Select: NM_001822
dbSNP: rs370140469
Type: single nucleotide variant
Location: chr2:174915125 (GRCh38)
Gene constraint: LOEUF 0.79 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.41 · 2 PDB
Residue 65: the sh2 domain

Full CHN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Duane retraction syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHN1 c.-160C>G Uncertain significance ★★ same condition
CHN1 c.-74C>T Uncertain significance ★★ same condition
CHN1 p.Ala27Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Asp440Gly Uncertain significance ★★ ⚠ same condition
CHN1 p.Lys260Asn Uncertain significance ★★ ⚠ same condition
CHN1 p.Thr167Ile Uncertain significance ★★ ⚠ same condition
CHN1 c.886+15G>A Benign ★★ same condition
CHN1 c.-68G>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/chn1-p-val65met (accessed [today's date]).

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