Is CHRDL2 p.Pro135Ser (c.403C>T) pathogenic?

CHRDL2 p.Pro135Ser (c.403C>T) is classified Uncertain significance in CHRDL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely benign (0.0885); Ultra-rare (popmax 0.0134%, eas).

How common is CHRDL2 p.Pro135Ser (c.403C>T) in the general population?

CHRDL2 p.Pro135Ser (c.403C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about CHRDL2 p.Pro135Ser (c.403C>T)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

CHRDL2 p.Pro135Ser

c.403C>T · VCV3267129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.114	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 3.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 34 kb · p 0.061 · regional, not allelic
Overall
CADD	18.32	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 0.0134% East Asian · 6/44,892 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000372% 6/1,614,130 alleles · ultra-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: CHRDL2
Protein: p.Pro135Ser
Coding: c.403C>T
MANE Select: NM_001278473
Type: single nucleotide variant
Location: chr11:74710878 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.31
Residue 135: the vwfc 2 domain

Full CHRDL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHRDL2 c.*3A>G Uncertain significance ★ same type
CHRDL2 p.Ala173Thr Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala205Thr Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala215Val Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala221Thr Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala360Thr Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala67Gly Uncertain significance ★ ⚠ same type
CHRDL2 p.Ala67Thr 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/chrdl2-p-pro135ser (accessed [today's date]).

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