Is CHAD p.Pro64Leu (c.191C>T) pathogenic?

CHAD p.Pro64Leu (c.191C>T) is classified Uncertain significance in CHAD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: ambiguous (0.4967); Ultra-rare (popmax 0.0165%, sas).

How common is CHAD p.Pro64Leu (c.191C>T) in the general population?

CHAD p.Pro64Leu (c.191C>T) is ultra-rare (popmax 0.0165%, sas) (gnomAD).

What do computational predictors say about CHAD p.Pro64Leu (c.191C>T)?

AlphaMissense predicts ambiguous (score 0.4967) — an in-silico prediction, not a clinical call.

CHAD p.Pro64Leu

c.191C>T · VCV3491825

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4967 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4967	ambiguous
REVEL	0.182	moderately benign-leaning
SaProt	LLR -11.99	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 10	GERP 0.52, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 3,512 bp · p 0.21 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% South Asian · 15/91,088 alleles

Filtering AF 0.0101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00144% 21/1,461,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0165%	6,073
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.000339%	295,010

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: CHAD
Protein: p.Pro64Leu
Coding: c.191C>T
MANE Select: NM_025149 · reported on NM_001267
Type: single nucleotide variant
Location: chr17:50468623 (GRCh38)

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

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/chad-p-pro64leu (accessed [today's date]).

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