Is CHRND p.Arg363Pro (c.1088G>C) pathogenic?

CHRND p.Arg363Pro (c.1088G>C) is classified Uncertain significance in CHRND (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.1544); Ultra-rare (popmax 0.011%, sas); Associated with lethal multiple pterygium syndrome.

What condition is associated with CHRND p.Arg363Pro (c.1088G>C)?

CHRND p.Arg363Pro (c.1088G>C) is associated with lethal multiple pterygium syndrome (ClinVar).

How common is CHRND p.Arg363Pro (c.1088G>C) in the general population?

CHRND p.Arg363Pro (c.1088G>C) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CHRND p.Arg363Pro (c.1088G>C)?

AlphaMissense predicts likely benign (score 0.1544) — an in-silico prediction, not a clinical call.

CHRND p.Arg363Pro

c.1088G>C · rs748108743 · VCV3003364

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1544 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lethal multiple pterygium syndrome

Computational evidence

Protein change
AlphaMissense	0.1544	likely benign
REVEL	0.395	indeterminate
SaProt	LLR -6.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 0.43	GERP -3.3, phastCons 0.003
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	15.6	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 0.011% South Asian · 10/91,066 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.000753% 11/1,461,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,107
European (non-Finnish)	8.47e-05%	1,179,994

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.Arg363Pro
Coding: c.1088G>C
MANE Select: NM_000751
dbSNP: rs748108743
Type: single nucleotide variant
Location: chr2:232533971 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB
Residue 363: an α-helix

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

Similar variants

CHRND p.Arg363His Uncertain significance ★ ⚠ 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-arg363pro (accessed [today's date]).

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