Is ADA p.Asp123His (c.367G>C) pathogenic?

ADA p.Asp123His (c.367G>C) is classified Uncertain significance in ADA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-21). AlphaMissense: likely benign (0.3226); Very rare (popmax 0.00544%, afr).

How common is ADA p.Asp123His (c.367G>C) in the general population?

ADA p.Asp123His (c.367G>C) is very rare (popmax 0.00544%, afr) (gnomAD).

What do computational predictors say about ADA p.Asp123His (c.367G>C)?

AlphaMissense predicts likely benign (score 0.3226) — an in-silico prediction, not a clinical call.

ADA p.Asp123His

c.367G>C · VCV4945127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00544%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3226	likely benign
REVEL	0.702	pathogenic-leaning
SaProt	LLR -9.57	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 32 kb · p 0.21 · regional, not allelic
Overall
CADD	26.6	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 0.00544% African / African-American · 4/73,584 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00106%

Overall 0.000256% 4/1,559,596 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: ADA
Protein: p.Asp123His
Coding: c.367G>C
MANE Select: NM_000022
Type: single nucleotide variant
Location: chr20:44625680 (GRCh38)
Gene constraint: LOEUF 1.184 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.81 · 2 PDB

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

Similar variants

ADA p.Asp123Asn Uncertain significance ★★ ⚠ same residue
ADA p.Asp123Ala Uncertain significance ★ ⚠ same residue
ADA p.Asp123fs Pathogenic/Likely pathogenic ★★ same residue
ADA c.1078+2T>A Likely pathogenic ★★★ same type
ADA c.219-2A>G Likely pathogenic ★★★ same type
ADA c.363-2A>G Likely pathogenic ★★★ same type
ADA c.606+1G>T Likely pathogenic ★★★ same type
ADA c.975+1G>A Pathogenic ★★★ 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/ada-p-asp123his (accessed [today's date]).

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