Is CHRDL1 p.Cys261Phe (c.782G>T) pathogenic?

CHRDL1 p.Cys261Phe (c.782G>T) is classified Pathogenic in CHRDL1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2012-02-10). AlphaMissense: likely pathogenic (0.9981); Very rare (popmax 0.000113%, nfe); Associated with megalocornea.

What condition is associated with CHRDL1 p.Cys261Phe (c.782G>T)?

CHRDL1 p.Cys261Phe (c.782G>T) is associated with megalocornea (ClinVar).

How common is CHRDL1 p.Cys261Phe (c.782G>T) in the general population?

CHRDL1 p.Cys261Phe (c.782G>T) is very rare (popmax 0.000113%, nfe) (gnomAD).

What do computational predictors say about CHRDL1 p.Cys261Phe (c.782G>T)?

AlphaMissense predicts likely pathogenic (score 0.9981) — an in-silico prediction, not a clinical call.

CHRDL1 p.Cys261Phe

c.782G>T · rs387906713 · VCV29958

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000113%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megalocornea

Computational evidence

Protein change
AlphaMissense	0.9981	likely pathogenic ✓ concordant with ClinVar · top 2% in CHRDL1
REVEL	0.984	strongly pathogenic-leaning
SaProt	LLR -17.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 116 kb · p 0.22 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C260F vs ClinVar C261F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000113% European (non-Finnish) · 1/883,415 alleles

Overall 9.22e-05% 1/1,084,441 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: CHRDL1
Protein: p.Cys261Phe
Coding: c.782G>T
MANE Select: NM_001143981
dbSNP: rs387906713
Type: single nucleotide variant
Location: chrX:110688800 (GRCh38)
Structure: AlphaFold pLDDT 69.79
Residue 261: the vwfc 3 domain

Full CHRDL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

megalocornea — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRDL1 c.1156+1G>T Pathogenic ★ same condition
CHRDL1 c.301+2T>G Pathogenic ★ same condition
CHRDL1 c.94+1G>A Pathogenic ★ same condition
CHRDL1 p.Arg77Ter Pathogenic ★ same condition
CHRDL1 p.Cys146Gly Likely pathogenic ★ same condition
CHRDL1 p.Lys326Ter Pathogenic ★ same condition
CHRDL1 p.Cys323Phe Uncertain significance ★ ⚠ same condition
CHRDL1 p.Glu69Asp Uncertain significance ★ ⚠ 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/chrdl1-p-cys261phe (accessed [today's date]).

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