Is CSAD p.Arg136Trp (c.406C>T) pathogenic?

CSAD p.Arg136Trp (c.406C>T) is classified Uncertain significance in CSAD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-03). AlphaMissense: ambiguous (0.5019); Ultra-rare (popmax 0.0657%, mid).

How common is CSAD p.Arg136Trp (c.406C>T) in the general population?

CSAD p.Arg136Trp (c.406C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about CSAD p.Arg136Trp (c.406C>T)?

AlphaMissense predicts ambiguous (score 0.5019) — an in-silico prediction, not a clinical call.

CSAD p.Arg136Trp

c.406C>T · rs140068701 · VCV2400789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5019 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Computational evidence

Protein change
AlphaMissense	0.5019	ambiguous
REVEL	0.371	indeterminate
SaProt	LLR -8.81	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.17, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.2 · regional, not allelic
Overall
CADD	33.0	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0413% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.04%

Overall 0.0413% 667/1,613,154 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.196%	510
Remaining individualsnot grpmax-eligible	0.0832%	1,201
Middle Easterngrpmax	0.0657%	1,521
European (non-Finnish)	0.0445%	2,247
Admixed American	0.0134%	7,486
African / African-American	0.012%	8,318
Finnishnot grpmax-eligible	0.0109%	9,143
South Asian	0.0044%	22,704

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg136Trp
Coding: c.406C>T
MANE Select: NM_001244705
dbSNP: rs140068701
Type: single nucleotide variant
Location: chr12:53171927 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 1 PDB
Residue 136: an α-helix

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

Similar variants

CSAD p.Arg136Gln 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
CSAD c.-33C>G 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-arg136trp (accessed [today's date]).

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