Is SI p.Thr122Ala (c.364A>G) pathogenic?

SI p.Thr122Ala (c.364A>G) is classified Conflicting classifications of pathogenicity in SI (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0781); Ultra-rare (popmax 0.0726%, sas); Associated with Inborn genetic diseases.

What condition is associated with SI p.Thr122Ala (c.364A>G)?

SI p.Thr122Ala (c.364A>G) is associated with Inborn genetic diseases (ClinVar).

How common is SI p.Thr122Ala (c.364A>G) in the general population?

SI p.Thr122Ala (c.364A>G) is ultra-rare (popmax 0.0726%, sas) (gnomAD).

What do computational predictors say about SI p.Thr122Ala (c.364A>G)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

SI p.Thr122Ala

c.364A>G · rs376103595 · VCV1553819

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0726%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -13.83	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.6, phastCons 0.99
Regional constraint	o/e 1.10	unconstrained · MANE · 97 kb · p 9.1e-07 · regional, not allelic
Overall
CADD	14.78	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 0.0726% South Asian · 66/90,852 alleles

Filtering AF 0.0585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0534%

Overall 0.00611% 98/1,603,492 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0726%	1,377
Remaining individualsnot grpmax-eligible	0.0129%	7,769
Admixed American	0.01%	9,997
African / African-American	0.00401%	24,947
European (non-Finnish)	0.00128%	78,030

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: SI
Protein: p.Thr122Ala
Coding: c.364A>G
MANE Select: NM_001041
dbSNP: rs376103595
Type: single nucleotide variant
Location: chr3:165069087 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.86 · 2 PDB
Residue 122: the 'isomaltase' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SI p.Thr122= Likely benign ★ same residue
SI p.Ala1654Asp Uncertain significance ★★ ⚠ same condition
SI p.Ala429Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala573Val Uncertain significance ★★ ⚠ same condition
SI p.Ala760Val Uncertain significance ★★ ⚠ same condition
SI p.Ala808Thr Uncertain significance ★★ ⚠ same condition
SI p.Ala826Asp Uncertain significance ★★ ⚠ same condition
SI p.Arg1078Gln Uncertain significance ★★ ⚠ same condition

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/si-p-thr122ala (accessed [today's date]).

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