Is CHRD p.Arg274Trp (c.820C>T) pathogenic?

CHRD p.Arg274Trp (c.820C>T) is classified Uncertain significance in CHRD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). AlphaMissense: likely benign (0.1208); Ultra-rare (popmax 0.0267%, amr).

How common is CHRD p.Arg274Trp (c.820C>T) in the general population?

CHRD p.Arg274Trp (c.820C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about CHRD p.Arg274Trp (c.820C>T)?

AlphaMissense predicts likely benign (score 0.1208) — an in-silico prediction, not a clinical call.

CHRD p.Arg274Trp

c.820C>T · rs142618898 · VCV2539580

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1208 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1208	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -8.16	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 1.7	GERP -0.57, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 9,100 bp · p 0.0047 · regional, not allelic
Overall
CADD	23.8	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 0.0267% Admixed American · 16/59,996 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00428% 69/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,750
African / African-American	0.0133%	7,493
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Finnishnot grpmax-eligible	0.0047%	21,281
East Asian	0.00446%	22,442
South Asian	0.00439%	22,769
European (non-Finnish)	0.00254%	39,334

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: CHRD
Protein: p.Arg274Trp
Coding: c.820C>T
MANE Select: NM_003741
dbSNP: rs142618898
Type: single nucleotide variant
Location: chr3:184382509 (GRCh38)
Gene constraint: LOEUF 0.763 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.95 · 3 PDB
Residue 274: the chrd 1 domain

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

Similar variants

CHRD p.Arg274Gln Uncertain significance ★ ⚠ same residue
CHRD p.Arg274Gly Uncertain significance ★ ⚠ same residue
CHRD p.Gln608= Benign ★★ same type
CHRD p.Gly387Ser Benign ★★ same type
CHRD p.Pro772= Benign ★★ same type
CHRD p.Thr301= Benign ★★ same type
CHRD p.Thr457Ser Likely benign ★★ same type
CHRD p.Ala251Glu Uncertain significance ★ ⚠ same type

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/chrd-p-arg274trp (accessed [today's date]).

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