Is TTN p.Ser3271Phe (c.9812C>T) pathogenic?

TTN p.Ser3271Phe (c.9812C>T) is classified Uncertain significance in TTN (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-16). AlphaMissense: likely benign (0.1981); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with TTN p.Ser3271Phe (c.9812C>T)?

TTN p.Ser3271Phe (c.9812C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is TTN p.Ser3271Phe (c.9812C>T) in the general population?

TTN p.Ser3271Phe (c.9812C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TTN p.Ser3271Phe (c.9812C>T)?

AlphaMissense predicts likely benign (score 0.1981) — an in-silico prediction, not a clinical call.

TTN p.Ser3271Phe

c.9812C>T · rs867536098 · VCV263487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1981	likely benign
REVEL	0.245	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 141 kb · p 0.23 · regional, not allelic
Overall
CADD	23.2	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,022 alleles

Overall 0.000186% 3/1,614,132 alleles · very rare exomes 3/1,461,824 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,022
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	8.47e-05%	1,179,997

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: TTN
Protein: p.Ser3271Phe
Coding: c.9812C>T
MANE Select: NM_001267550
dbSNP: rs867536098
Type: single nucleotide variant
Location: chr2:178764703 (GRCh38)
Gene constraint: LOEUF 0.479 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Residue 3271: the ig-like 19 domain

Full TTN 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

Similar variants

TTN p.Ser3271= Likely benign ★★ same residue
TTN p.Ser3271Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TTN c.107377+1G>C Pathogenic/Likely pathogenic ★★ same condition
TTN c.54190+1G>A Pathogenic/Likely pathogenic ★★ same condition
TTN c.54811+1G>A Likely pathogenic ★★ same condition
TTN c.57112-1G>A Likely pathogenic ★★ same condition
TTN c.58732+2T>C Likely pathogenic ★★ same condition
TTN c.95723-2A>C 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/ttn-p-ser3271phe (accessed [today's date]).

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