Is ADSS2 p.Val304Ile (c.910G>A) pathogenic?

ADSS2 p.Val304Ile (c.910G>A) is classified Uncertain significance in ADSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.7766); Ultra-rare (popmax 0.038%, nfe).

How common is ADSS2 p.Val304Ile (c.910G>A) in the general population?

ADSS2 p.Val304Ile (c.910G>A) is ultra-rare (popmax 0.038%, nfe) (gnomAD).

What do computational predictors say about ADSS2 p.Val304Ile (c.910G>A)?

AlphaMissense predicts likely pathogenic (score 0.7766) — an in-silico prediction, not a clinical call.

ADSS2 p.Val304Ile

c.910G>A · rs201194182 · VCV2591808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7766 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.038%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7766	likely pathogenic
REVEL	0.482	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
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 0.38	unconstrained · MANE · 1,445 bp · p 7.6e-08 · regional, not allelic
Overall
CADD	27.3	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 0.038% European (non-Finnish) · 448/1,179,888 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0338%

Overall 0.0294% 474/1,613,836 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.038%	2,634
Remaining individualsnot grpmax-eligible	0.0208%	4,807
Admixed American	0.0117%	8,568
African / African-American	0.00666%	15,010
Finnishnot grpmax-eligible	0.00156%	64,018

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: ADSS2
Protein: p.Val304Ile
Coding: c.910G>A
MANE Select: NM_001126
dbSNP: rs201194182
Type: single nucleotide variant
Location: chr1:244418795 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 92.90 · 1 PDB
Residue 304: a β-strand

Full ADSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADSS2 p.Ala349Thr Uncertain significance ★ ⚠ same type
ADSS2 p.Ala390Val Uncertain significance ★ ⚠ same type
ADSS2 p.Ala417Ser Uncertain significance ★ ⚠ same type
ADSS2 p.Ala417Val Uncertain significance ★ ⚠ same type
ADSS2 p.Asn409Lys Uncertain significance ★ ⚠ same type
ADSS2 p.Asn90Lys Uncertain significance ★ ⚠ same type
ADSS2 p.Asp17Asn Uncertain significance ★ ⚠ same type
ADSS2 p.Asp381Asn 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/adss2-p-val304ile (accessed [today's date]).

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