Is ADSS1 p.Arg417Trp (c.1249A>T) pathogenic?

ADSS1 p.Arg417Trp (c.1249A>T) is classified Uncertain significance in ADSS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-02). AlphaMissense: ambiguous (0.4193); Very rare (popmax 0.00534%, afr).

How common is ADSS1 p.Arg417Trp (c.1249A>T) in the general population?

ADSS1 p.Arg417Trp (c.1249A>T) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about ADSS1 p.Arg417Trp (c.1249A>T)?

AlphaMissense predicts ambiguous (score 0.4193) — an in-silico prediction, not a clinical call.

ADSS1 p.Arg417Trp

c.1249A>T · rs1470435167 · VCV1682025

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Computational evidence

Protein change
AlphaMissense	0.4193	ambiguous
REVEL	0.459	indeterminate
SaProt	LLR -16.20	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.8, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 23 kb · p 0.77 · regional, not allelic
Overall
CADD	24.4	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 0.00534% African / African-American · 4/74,932 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000248% 4/1,613,694 alleles · very rare

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: ADSS1
Protein: p.Arg417Trp
Coding: c.1249A>T
MANE Select: NM_152328
dbSNP: rs1470435167
Type: single nucleotide variant
Location: chr14:104746313 (GRCh38)
Gene constraint: LOEUF 1.245 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.10

Full ADSS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADSS1 c.949-2A>G Likely pathogenic ★★ same type
ADSS1 p.Asp261Asn Pathogenic/Likely pathogenic ★★ same type
ADSS1 p.Gln323Ter Pathogenic/Likely pathogenic ★★ same type
ADSS1 c.193-4823C>A Uncertain significance ★★ same type
ADSS1 c.193-4836G>A Uncertain significance ★★ same type
ADSS1 c.193-4838G>A Uncertain significance ★★ same type
ADSS1 c.193-4866C>T Uncertain significance ★★ same type
ADSS1 c.193-4916C>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/adss1-p-arg417trp (accessed [today's date]).

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