Is CHRND p.Lys89Asn (c.267G>C) pathogenic?

CHRND p.Lys89Asn (c.267G>C) is classified Conflicting classifications of pathogenicity in CHRND (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-01-31). AlphaMissense: ambiguous (0.3588); Rare (popmax 0.199%, sas); Associated with lethal multiple pterygium syndrome.

What condition is associated with CHRND p.Lys89Asn (c.267G>C)?

CHRND p.Lys89Asn (c.267G>C) is associated with lethal multiple pterygium syndrome, congenital myasthenic syndrome (ClinVar).

How common is CHRND p.Lys89Asn (c.267G>C) in the general population?

CHRND p.Lys89Asn (c.267G>C) is rare (popmax 0.199%, sas) (gnomAD).

What do computational predictors say about CHRND p.Lys89Asn (c.267G>C)?

AlphaMissense predicts ambiguous (score 0.3588) — an in-silico prediction, not a clinical call.

CHRND p.Lys89Asn

c.267G>C · rs545298641 · VCV895989

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3588 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.199%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

lethal multiple pterygium syndrome

Computational evidence

Protein change
AlphaMissense	0.3588	ambiguous
REVEL	0.178	moderately benign-leaning
SaProt	LLR -9.78	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.2	GERP -0.49, phastCons 0.98
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.199% South Asian · 181/91,086 alleles

Filtering AF 0.175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.0115% 186/1,614,218 alleles · rare exomes 176/1,461,894 · genomes 10/152,324 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.199%	503
Remaining individualsnot grpmax-eligible	0.0064%	15,628
African / African-American	0.00133%	75,056

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: CHRND
Protein: p.Lys89Asn
Coding: c.267G>C
MANE Select: NM_000751
dbSNP: rs545298641
Type: single nucleotide variant
Location: chr2:232528285 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB

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

Disease context

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

Also linked: congenital myasthenic syndrome

Similar variants

CHRND p.Lys89= Likely benign ★ same residue
CHRND c.1252+1G>A Pathogenic/Likely pathogenic ★★ same condition
CHRND c.821-2A>C Pathogenic/Likely pathogenic ★★ same condition
CHRND c.933-2A>G Likely pathogenic ★★ same condition
CHRND p.Arg336Gln Likely pathogenic ★★ same condition
CHRND p.Arg43Trp Pathogenic/Likely pathogenic ★★ same condition
CHRND p.Cys257Arg Pathogenic/Likely pathogenic ★★ same condition
CHRND p.Trp78Ter Pathogenic ★★ 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/chrnd-p-lys89asn (accessed [today's date]).

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