Is ADM2 p.Ser43Thr (c.128G>C) pathogenic?

ADM2 p.Ser43Thr (c.128G>C) is classified Likely benign in ADM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.0614); Very rare (popmax 0.000181%, nfe).

How common is ADM2 p.Ser43Thr (c.128G>C) in the general population?

ADM2 p.Ser43Thr (c.128G>C) is very rare (popmax 0.000181%, nfe) (gnomAD).

What do computational predictors say about ADM2 p.Ser43Thr (c.128G>C)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

ADM2 p.Ser43Thr

c.128G>C · rs549854733 · VCV3089493

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000181%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -3.3
Regional constraint	o/e 1.12	unconstrained · MANE · 1,052 bp · p 0.088 · regional, not allelic
Overall
CADD	0.022	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 0.000181% European (non-Finnish) · 2/1,107,456 alleles

Filtering AF 3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000152% 2/1,314,228 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: ADM2
Protein: p.Ser43Thr
Coding: c.128G>C
MANE Select: NM_001253845
dbSNP: rs549854733
Type: single nucleotide variant
Location: chr22:50482584 (GRCh38)
Gene constraint: LOEUF 1.901 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.44 · 2 PDB
Residue 43: the 'disordered' region

Full ADM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADM2 p.Arg83= Benign ★★ same type
ADM2 p.Ala54Thr Uncertain significance ★ ⚠ same type
ADM2 p.Ala75Val Uncertain significance ★ ⚠ same type
ADM2 p.Arg107Gly Uncertain significance ★ ⚠ same type
ADM2 p.Arg133Gln Uncertain significance ★ ⚠ same type
ADM2 p.Arg42Trp Uncertain significance ★ ⚠ same type
ADM2 p.Arg56Gln Uncertain significance ★ ⚠ same type
ADM2 p.Arg87His 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/adm2-p-ser43thr (accessed [today's date]).

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