Is CHRND p.Ser274Arg (c.822T>G) pathogenic?

CHRND p.Ser274Arg (c.822T>G) is classified Uncertain significance in CHRND (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-16). AlphaMissense: likely pathogenic (0.9575); Very rare (popmax 0.00892%, eas); Associated with lethal multiple pterygium syndrome.

What condition is associated with CHRND p.Ser274Arg (c.822T>G)?

CHRND p.Ser274Arg (c.822T>G) is associated with lethal multiple pterygium syndrome (ClinVar).

How common is CHRND p.Ser274Arg (c.822T>G) in the general population?

CHRND p.Ser274Arg (c.822T>G) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about CHRND p.Ser274Arg (c.822T>G)?

AlphaMissense predicts likely pathogenic (score 0.9575) — an in-silico prediction, not a clinical call.

CHRND p.Ser274Arg

c.822T>G · rs746002657 · VCV2440046

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

lethal multiple pterygium syndrome

Computational evidence

Protein change
AlphaMissense	0.9575	likely pathogenic · top 8% in CHRND
REVEL	0.634	indeterminate
SaProt	LLR -13.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.31	acceptor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.29	loss · gain 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.22	GERP -3.4, phastCons 0.64
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	21.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00892% East Asian · 4/44,842 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000274% 4/1,459,322 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: CHRND
Protein: p.Ser274Arg
Coding: c.822T>G
MANE Select: NM_000751
dbSNP: rs746002657
Type: single nucleotide variant
Location: chr2:232531353 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB
Residue 274: 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 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
CHRND p.Trp83Ter 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-ser274arg (accessed [today's date]).

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