Is TTR p.Phe84Ser (c.251T>C) pathogenic?

TTR p.Phe84Ser (c.251T>C) is classified Pathogenic in TTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-10). AlphaMissense: likely pathogenic (0.9386); Absent from gnomAD v4.1; Associated with amyloidosis, hereditary systemic 1.

What condition is associated with TTR p.Phe84Ser (c.251T>C)?

TTR p.Phe84Ser (c.251T>C) is associated with amyloidosis, hereditary systemic 1 (ClinVar).

How common is TTR p.Phe84Ser (c.251T>C) in the general population?

TTR p.Phe84Ser (c.251T>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary ATTR amyloidosis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TTR p.Phe84Ser (c.251T>C)?

AlphaMissense predicts likely pathogenic (score 0.9386) — an in-silico prediction, not a clinical call.

TTR p.Phe84Ser

c.251T>C · rs121918099 · VCV1067500

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9386 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyloidosis, hereditary systemic 1

Computational evidence

Protein change
AlphaMissense	0.9386	likely pathogenic ✓ concordant with ClinVar · top 7% in TTR
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -10.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 6,769 bp · p 0.00021 · regional, not allelic
Overall
CADD	26.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TTR
Protein: p.Phe84Ser
Coding: c.251T>C
MANE Select: NM_000371
dbSNP: rs121918099
Type: single nucleotide variant
Location: chr18:31595170 (GRCh38)
Gene constraint: LOEUF 1.049 · pLI 0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 88.74 · 493 PDB
Residue 84: a UniProt-annotated variant site (in amyld1; amyloid polyneuropathy)

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

Disease context

amyloidosis, hereditary systemic 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary ATTR amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

TTR p.Phe84Leu Pathogenic ★★ ⚠ same residue
TTR p.Phe84Tyr Likely pathogenic ★ ⚠ same residue
TTR p.Phe84Ile Likely pathogenic ★ ⚠ 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-phe84ser (accessed [today's date]).

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