Is CHRND p.Pro271Leu (c.812C>T) pathogenic?

CHRND p.Pro271Leu (c.812C>T) is classified Uncertain significance in CHRND (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.9205); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with CHRND p.Pro271Leu (c.812C>T)?

CHRND p.Pro271Leu (c.812C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CHRND p.Pro271Leu (c.812C>T) in the general population?

CHRND p.Pro271Leu (c.812C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CHRND p.Pro271Leu (c.812C>T)?

AlphaMissense predicts likely pathogenic (score 0.9205) — an in-silico prediction, not a clinical call.

CHRND p.Pro271Leu

c.812C>T · VCV4615365

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9205 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9205	likely pathogenic
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -16.89	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 9,093 bp · p 0.12 · regional, not allelic
Overall
CADD	28.8	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 0.0022% South Asian · 2/91,072 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000205% 3/1,461,798 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,536
European (non-Finnish)	8.47e-05%	1,179,997

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.Pro271Leu
Coding: c.812C>T
MANE Select: NM_000751
Type: single nucleotide variant
Location: chr2:232530131 (GRCh38)
Gene constraint: LOEUF 0.848 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.21 · 25 PDB
Residue 271: a UniProt-annotated variant site (in cms3b; burst duration was decreased and disassociation of ach was increased resulting in brief channel opening episodes; shows abnormal association with alpha chrna1 subunit resulting in a decreased number of fully assembled achrs)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHRND p.Pro271= Likely benign ★★ same residue
CHRND p.Pro271Gln Likely pathogenic ★ same residue
CHRND p.Arg102Cys Uncertain significance ★★ ⚠ same condition
CHRND p.Arg102His Uncertain significance ★★ ⚠ same condition
CHRND p.Arg148His Uncertain significance ★★ ⚠ same condition
CHRND p.Arg191His Uncertain significance ★★ ⚠ same condition
CHRND p.Arg298Cys Uncertain significance ★★ ⚠ same condition
CHRND p.Arg30Gln 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/chrnd-p-pro271leu (accessed [today's date]).

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