Is TMTC3 p.Arg656Ter (c.1966C>T) pathogenic?

TMTC3 p.Arg656Ter (c.1966C>T) is classified Pathogenic in TMTC3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-14). Very rare (popmax 0.00135%, afr); Associated with lissencephaly 8.

What condition is associated with TMTC3 p.Arg656Ter (c.1966C>T)?

TMTC3 p.Arg656Ter (c.1966C>T) is associated with lissencephaly 8 (ClinVar).

How common is TMTC3 p.Arg656Ter (c.1966C>T) in the general population?

TMTC3 p.Arg656Ter (c.1966C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

TMTC3 p.Arg656Ter

c.1966C>T · rs2041490074 · VCV1456984

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

lissencephaly 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (14 of 14) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.78	GERP 0.18, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00135% African / African-American · 1/74,194 alleles

Filtering AF 0.000248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.0005% 8/1,599,148 alleles · very rare exomes 8/1,447,324 · genomes 0/151,824 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,194
European (non-Finnish)	0.000596%	167,704

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: TMTC3
Protein: p.Arg656Ter
Coding: c.1966C>T
MANE Select: NM_181783
dbSNP: rs2041490074
Type: single nucleotide variant
Location: chr12:88194870 (GRCh38)
Gene constraint: LOEUF 0.721 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.83

Full TMTC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

lissencephaly 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMTC3 p.Arg656Gln Uncertain significance ★ same residue
TMTC3 p.Arg319Ter Pathogenic/Likely pathogenic ★★ same condition
TMTC3 p.Asp561Asn Uncertain significance ★★ same condition
TMTC3 p.Glu463Ala Uncertain significance ★★ same condition
TMTC3 p.Ile4Val Uncertain significance ★★ same condition
TMTC3 p.Tyr20Cys Uncertain significance ★★ same condition
TMTC3 c.1432+1G>A Likely pathogenic ★ same condition
TMTC3 p.Asp317Gly 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/tmtc3-p-arg656ter (accessed [today's date]).

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