Is CHRND p.Arg407Trp (c.1219C>T) pathogenic?

CHRND p.Arg407Trp (c.1219C>T) is classified Uncertain significance in CHRND (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-23). AlphaMissense: ambiguous (0.5025); Very rare (popmax 0.00167%, amr); Associated with lethal multiple pterygium syndrome.

What condition is associated with CHRND p.Arg407Trp (c.1219C>T)?

CHRND p.Arg407Trp (c.1219C>T) is associated with lethal multiple pterygium syndrome (ClinVar).

How common is CHRND p.Arg407Trp (c.1219C>T) in the general population?

CHRND p.Arg407Trp (c.1219C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHRND p.Arg407Trp (c.1219C>T)?

AlphaMissense predicts ambiguous (score 0.5025) — an in-silico prediction, not a clinical call.

CHRND p.Arg407Trp

c.1219C>T · rs766721840 · VCV1008543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5025 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

lethal multiple pterygium syndrome

Computational evidence

Protein change
AlphaMissense	0.5025	ambiguous
REVEL	0.662	pathogenic-leaning
SaProt	LLR -8.36	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP 0.76, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	25.0	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 0.00167% Admixed American · 1/60,034 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00123% 18/1,461,772 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Admixed Americangrpmax	0.00167%	60,034
Remaining individualsnot grpmax-eligible	0.0016%	62,510
Finnishnot grpmax-eligible	0.00156%	63,930
South Asian	0.0011%	91,090
European (non-Finnish)	0.00102%	98,337

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg407Trp
Coding: c.1219C>T
MANE Select: NM_000751
dbSNP: rs766721840
Type: single nucleotide variant
Location: chr2:232534102 (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

Similar variants

CHRND p.Arg407Gln Uncertain significance ★★ ⚠ same residue
CHRND p.Arg407= 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

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-arg407trp (accessed [today's date]).

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