Is TTR p.Arg124= (c.372C>G) pathogenic?

TTR p.Arg124= (c.372C>G) is classified Benign/Likely benign in TTR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-15). Rare (popmax 0.222%, sas); Associated with Cardiovascular phenotype.

What condition is associated with TTR p.Arg124= (c.372C>G)?

TTR p.Arg124= (c.372C>G) is associated with Cardiovascular phenotype, amyloidosis, hereditary systemic 1 (ClinVar).

How common is TTR p.Arg124= (c.372C>G) in the general population?

TTR p.Arg124= (c.372C>G) is rare (popmax 0.222%, sas) (gnomAD).

TTR p.Arg124=

c.372C>G · rs780119793 · VCV517738

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.222%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.033	GERP -3.6, phastCons 0.001
Overall
CADD	1.137	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.222% South Asian · 202/91,092 alleles

Filtering AF 0.197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.187%

Overall 0.0128% 207/1,614,124 alleles · rare exomes 199/1,461,878 · genomes 8/152,246 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.222%	451
Remaining individualsnot grpmax-eligible	0.008%	12,498

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: TTR
Protein: p.Arg124=
Coding: c.372C>G
MANE Select: NM_000371
dbSNP: rs780119793
Type: single nucleotide variant
Location: chr18:31598603 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.74 · 493 PDB
Residue 124: a β-strand; a UniProt-annotated variant site (in)

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: amyloidosis, hereditary systemic 1

Similar variants

TTR p.Arg124Cys Uncertain significance ★★ ⚠ same residue
TTR p.Arg124His Conflicting classifications of pathogenicity ★ ⚠ same residue
TTR p.Arg124Leu Uncertain significance ★ ⚠ same residue
TTR p.Arg124Pro Uncertain significance ★ ⚠ same residue
TTR p.Ala117Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
TTR p.Ala39Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TTR p.Ala56Pro Pathogenic/Likely pathogenic ★★ same condition
TTR p.Ala65Asp Pathogenic/Likely pathogenic ★★ ⚠ 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/ttr-p-arg124 (accessed [today's date]).

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