Is ADSS2 p.Val57Met (c.169G>A) pathogenic?

ADSS2 p.Val57Met (c.169G>A) is classified Uncertain significance in ADSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: likely pathogenic (0.9571); Very rare (popmax 0.00134%, afr).

How common is ADSS2 p.Val57Met (c.169G>A) in the general population?

ADSS2 p.Val57Met (c.169G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ADSS2 p.Val57Met (c.169G>A)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

ADSS2 p.Val57Met

c.169G>A · VCV3502934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic
REVEL	0.414	indeterminate
SaProt	LLR -14.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -0.17, phastCons 1
Regional constraint	o/e 0.40	unconstrained · MANE · 14 kb · p 2.3e-07 · regional, not allelic
Overall
CADD	28.4	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 0.00134% African / African-American · 1/74,800 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,610,218 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,800
European (non-Finnish)	0.00017%	589,112

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.Val57Met
Coding: c.169G>A
MANE Select: NM_001126
Type: single nucleotide variant
Location: chr1:244451649 (GRCh38)
Gene constraint: LOEUF 0.646 · pLI 0.14 (gnomAD)
Structure: AlphaFold pLDDT 92.90 · 1 PDB
Residue 57: a β-strand

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

Similar variants

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ADSS2 p.Ala417Val Uncertain significance ★ ⚠ same type
ADSS2 p.Asn409Lys Uncertain significance ★ ⚠ same type
ADSS2 p.Asn90Lys Uncertain significance ★ ⚠ same type
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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-val57met (accessed [today's date]).

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