Is TDRD7 p.Ser67Pro (c.199T>C) pathogenic?

TDRD7 p.Ser67Pro (c.199T>C) is classified Uncertain significance in TDRD7 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). AlphaMissense: likely benign (0.2331); Ultra-rare (popmax 0.0125%, nfe); Associated with cataract 36.

What condition is associated with TDRD7 p.Ser67Pro (c.199T>C)?

TDRD7 p.Ser67Pro (c.199T>C) is associated with cataract 36 (ClinVar).

How common is TDRD7 p.Ser67Pro (c.199T>C) in the general population?

TDRD7 p.Ser67Pro (c.199T>C) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about TDRD7 p.Ser67Pro (c.199T>C)?

AlphaMissense predicts likely benign (score 0.2331) — an in-silico prediction, not a clinical call.

TDRD7 p.Ser67Pro

c.199T>C · rs148039648 · VCV912624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2331 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cataract 36

Computational evidence

Protein change
AlphaMissense	0.2331	likely benign
REVEL	0.123	moderately benign-leaning
SaProt	LLR -12.70	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 2.3, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 3,585 bp · p 9.7e-05 · regional, not allelic
Overall
CADD	24.8	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 0.0125% European (non-Finnish) · 147/1,179,866 alleles

Filtering AF 0.0108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.00985% 159/1,613,428 alleles · ultra-rare exomes 152/1,461,302 · genomes 7/152,126 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	8,026
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,865
Finnishnot grpmax-eligible	0.00942%	10,618
Remaining individualsnot grpmax-eligible	0.0048%	20,821

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: TDRD7
Protein: p.Ser67Pro
Coding: c.199T>C
MANE Select: NM_014290
dbSNP: rs148039648
Type: single nucleotide variant
Location: chr9:97428664 (GRCh38)
Gene constraint: LOEUF 0.521 · pLI 0.37 (gnomAD)
Structure: AlphaFold pLDDT 73.60 · 1 PDB
Residue 67: the hth ost-type 1 domain

Full TDRD7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 36 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TDRD7 p.Ala651Thr Uncertain significance ★★ ⚠ same condition
TDRD7 p.Ala895Thr Uncertain significance ★★ ⚠ same condition
TDRD7 p.Ala958Thr Uncertain significance ★★ ⚠ same condition
TDRD7 p.Arg1013Gln Uncertain significance ★★ ⚠ same condition
TDRD7 p.Arg99Cys Uncertain significance ★★ ⚠ same condition
TDRD7 p.Asn631Ser Uncertain significance ★★ ⚠ same condition
TDRD7 p.Glu63Asp Uncertain significance ★★ ⚠ same condition
TDRD7 p.His421Asn 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/tdrd7-p-ser67pro (accessed [today's date]).

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