Is CSAD p.Pro419Arg (c.1256C>G) pathogenic?

CSAD p.Pro419Arg (c.1256C>G) is classified Uncertain significance in CSAD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely benign (0.1019); Rare (popmax 0.182%, mid).

How common is CSAD p.Pro419Arg (c.1256C>G) in the general population?

CSAD p.Pro419Arg (c.1256C>G) is rare (popmax 0.182%, mid) (gnomAD).

What do computational predictors say about CSAD p.Pro419Arg (c.1256C>G)?

AlphaMissense predicts likely benign (score 0.1019) — an in-silico prediction, not a clinical call.

CSAD p.Pro419Arg

c.1256C>G · rs140401098 · VCV2341003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1019 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.182%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1019	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP -0.18, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.2 · regional, not allelic
Overall
CADD	25.0	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 0.182% Middle Eastern · 11/6,058 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0787%

Overall 0.0114% 184/1,611,578 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.182%	551
South Asian	0.0465%	2,151
Admixed American	0.0285%	3,505
Remaining individualsnot grpmax-eligible	0.0144%	6,937
European (non-Finnish)	0.00865%	11,558
African / African-American	0.004%	25,003

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: CSAD
Protein: p.Pro419Arg
Coding: c.1256C>G
MANE Select: NM_001244705
dbSNP: rs140401098
Type: single nucleotide variant
Location: chr12:53159675 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 1 PDB
Residue 419: an α-helix

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

Similar variants

CSAD p.Pro419Ala Uncertain significance ★ ⚠ same residue
CSAD p.Pro419Thr Uncertain significance ★ ⚠ same residue
CSAD p.Ala103= Benign ★★ same type
CSAD p.Ala199= Benign ★★ same type
CSAD p.Glu50= Benign ★★ same type
CSAD c.-21C>T Uncertain significance ★ same type
CSAD c.-24G>T Uncertain significance ★ same type
CSAD c.-27C>T 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/csad-p-pro419arg (accessed [today's date]).

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