Is TTR p.Arg41= (c.121C>A) pathogenic?

TTR p.Arg41= (c.121C>A) is classified Likely benign in TTR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-29). Very rare (popmax 0.00134%, afr); Associated with carpal tunnel syndrome 1.

What condition is associated with TTR p.Arg41= (c.121C>A)?

TTR p.Arg41= (c.121C>A) is associated with carpal tunnel syndrome 1, hyperthyroxinemia, dystransthyretinemic, amyloidosis, hereditary systemic 1 (ClinVar).

How common is TTR p.Arg41= (c.121C>A) in the general population?

TTR p.Arg41= (c.121C>A) is very rare (popmax 0.00134%, afr) (gnomAD).

TTR p.Arg41=

c.121C>A · rs1004021945 · VCV698845

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

carpal tunnel syndrome 1

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 4.1	GERP -0.22, phastCons 1
Overall
CADD	9.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,874 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,613,914 alleles · very rare exomes 3/1,461,806 · genomes 2/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,874
European (non-Finnish)	0.000339%	294,995

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.Arg41=
Coding: c.121C>A
MANE Select: NM_000371
dbSNP: rs1004021945
Type: single nucleotide variant
Location: chr18:31592947 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.74 · 493 PDB
Residue 41: a turn

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

Disease context

carpal tunnel syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperthyroxinemia, dystransthyretinemic amyloidosis, hereditary systemic 1

Similar variants

TTR p.Arg41Gln Uncertain significance ★★ ⚠ same residue
TTR p.Arg41Pro Uncertain significance ★ ⚠ same residue
TTR p.Arg41Ter 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
TTR p.Ala65Thr 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-arg41 (accessed [today's date]).

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