Is TTLL5 p.Arg447Pro (c.1340G>C) pathogenic?

TTLL5 p.Arg447Pro (c.1340G>C) is classified Uncertain significance in TTLL5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-11). AlphaMissense: ambiguous (0.487); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with TTLL5 p.Arg447Pro (c.1340G>C)?

TTLL5 p.Arg447Pro (c.1340G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TTLL5 p.Arg447Pro (c.1340G>C) in the general population?

TTLL5 p.Arg447Pro (c.1340G>C) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about TTLL5 p.Arg447Pro (c.1340G>C)?

AlphaMissense predicts ambiguous (score 0.487) — an in-silico prediction, not a clinical call.

TTLL5 p.Arg447Pro

c.1340G>C · rs745935869 · VCV1937263

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.487 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.487	ambiguous
REVEL	0.149	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 291 kb · p 0.36 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.0117% Admixed American · 7/60,010 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000434% 7/1,613,924 alleles · ultra-rare exomes 7/1,461,646 · genomes 0/152,278 · joint denominator

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: TTLL5
Protein: p.Arg447Pro
Coding: c.1340G>C
MANE Select: NM_015072
dbSNP: rs745935869
Type: single nucleotide variant
Location: chr14:75745153 (GRCh38)
Gene constraint: LOEUF 0.888 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.56 · 1 PDB
Residue 447: the 'c-mtbd region' region

Full TTLL5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TTLL5 p.Arg447Gln Uncertain significance ★★ ⚠ same residue
TTLL5 p.Arg447Trp Uncertain significance ★★ ⚠ same residue
TTLL5 p.Arg447Gly Uncertain significance ★ ⚠ same residue
TTLL5 p.Ala1042Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Ala328Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Ala446Val Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Gln Uncertain significance ★★ ⚠ same condition
TTLL5 p.Arg1023Trp Uncertain significance ★★ ⚠ 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/ttll5-p-arg447pro (accessed [today's date]).

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