Is CSAD p.Val123Met (c.367G>A) pathogenic?

CSAD p.Val123Met (c.367G>A) is classified Uncertain significance in CSAD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.6201); Ultra-rare (popmax 0.015%, amr).

How common is CSAD p.Val123Met (c.367G>A) in the general population?

CSAD p.Val123Met (c.367G>A) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about CSAD p.Val123Met (c.367G>A)?

AlphaMissense predicts likely pathogenic (score 0.6201) — an in-silico prediction, not a clinical call.

CSAD p.Val123Met

c.367G>A · VCV4656934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6201 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6201	likely pathogenic
REVEL	0.663	pathogenic-leaning
SaProt	LLR -11.73	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 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.2 · regional, not allelic
Overall
CADD	31.0	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 0.015% Admixed American · 9/59,976 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.0013% 21/1,613,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,664
Remaining individualsnot grpmax-eligible	0.0048%	20,825
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000678%	147,490

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.Val123Met
Coding: c.367G>A
MANE Select: NM_001244705
Type: single nucleotide variant
Location: chr12:53171966 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 1 PDB
Residue 123: an α-helix

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

Similar variants

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
CSAD c.-48A>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-val123met (accessed [today's date]).

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