Is CSAD p.Phe481Ile (c.1441T>A) pathogenic?

CSAD p.Phe481Ile (c.1441T>A) is classified Uncertain significance in CSAD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: ambiguous (0.3657); Rare (popmax 0.116%, mid).

How common is CSAD p.Phe481Ile (c.1441T>A) in the general population?

CSAD p.Phe481Ile (c.1441T>A) is rare (popmax 0.116%, mid) (gnomAD).

What do computational predictors say about CSAD p.Phe481Ile (c.1441T>A)?

AlphaMissense predicts ambiguous (score 0.3657) — an in-silico prediction, not a clinical call.

CSAD p.Phe481Ile

c.1441T>A · rs201988379 · VCV2509440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3657 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Computational evidence

Protein change
AlphaMissense	0.3657	ambiguous
REVEL	0.571	indeterminate
SaProt	LLR -11.05	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.2 · regional, not allelic
Overall
CADD	27.1	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 0.116% Middle Eastern · 7/6,060 alleles

Filtering AF 0.0713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0657%

Overall 0.0328% 529/1,613,402 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.116%	866
South Asian	0.0867%	1,153
Remaining individualsnot grpmax-eligible	0.0592%	1,688
European (non-Finnish)	0.0336%	2,980
Admixed American	0.00834%	11,989
African / African-American	0.00538%	18,602
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,594

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.Phe481Ile
Coding: c.1441T>A
MANE Select: NM_001244705
dbSNP: rs201988379
Type: single nucleotide variant
Location: chr12:53158552 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 1 PDB
Residue 481: 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-phe481ile (accessed [today's date]).

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