Is ADIG p.Ser49Arg (c.145A>C) pathogenic?

ADIG p.Ser49Arg (c.145A>C) is classified Uncertain significance in ADIG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-22). AlphaMissense: likely benign (0.1717); Very rare (popmax 0.00594%, nfe).

How common is ADIG p.Ser49Arg (c.145A>C) in the general population?

ADIG p.Ser49Arg (c.145A>C) is very rare (popmax 0.00594%, nfe) (gnomAD).

What do computational predictors say about ADIG p.Ser49Arg (c.145A>C)?

AlphaMissense predicts likely benign (score 0.1717) — an in-silico prediction, not a clinical call.

ADIG p.Ser49Arg

c.145A>C · rs376449177 · VCV3089381

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1717 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00594%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1717	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -6.94	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 3.3	GERP -3.2, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 4,893 bp · p 0.033 · regional, not allelic
Overall
CADD	8.095	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00594% European (non-Finnish) · 70/1,178,188 alleles

Filtering AF 0.00479% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00439%

Overall 0.00441% 71/1,609,566 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00594%	16,831
African / African-American	0.00134%	74,900

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: ADIG
Protein: p.Ser49Arg
Coding: c.145A>C
MANE Select: NM_001393816
dbSNP: rs376449177
Type: single nucleotide variant
Location: chr20:38586049 (GRCh38)
Gene constraint: LOEUF 1.845 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.94

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

Similar variants

ADIG c.20C>A Uncertain significance ★ same type
ADIG p.Arg36His Uncertain significance ★ ⚠ same type
ADIG p.Arg77Lys Uncertain significance ★ ⚠ same type
ADIG p.Leu38Phe Uncertain significance ★ ⚠ same type
ADIG p.Leu39Phe Uncertain significance ★ ⚠ same type
ADIG p.Phe64Val Uncertain significance ★ ⚠ same type
ADIG p.Pro24Ser Uncertain significance ★ ⚠ same type
ADIG p.Pro7Leu 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/adig-p-ser49arg (accessed [today's date]).

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