Is TRAF7 p.Leu640Pro (c.1919T>C) pathogenic?

TRAF7 p.Leu640Pro (c.1919T>C) is classified Conflicting classifications of pathogenicity in TRAF7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-04-07). AlphaMissense: likely pathogenic (0.989); Absent from gnomAD v4.1; Associated with TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome.

How common is TRAF7 p.Leu640Pro (c.1919T>C) in the general population?

TRAF7 p.Leu640Pro (c.1919T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRAF7 p.Leu640Pro (c.1919T>C)?

AlphaMissense predicts likely pathogenic (score 0.989) — an in-silico prediction, not a clinical call.

TRAF7 p.Leu640Pro

Q: What condition is associated with TRAF7 p.Leu640Pro (c.1919T>C)?

TRAF7 p.Leu640Pro (c.1919T>C) is associated with TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome, cardiac, facial, and digital anomalies with developmental delay (ClinVar).

c.1919T>C · rs2141299157 · VCV1700055

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome

Computational evidence

Protein change
AlphaMissense	0.989	likely pathogenic
REVEL	0.285	benign-leaning
SaProt	LLR -9.19	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Regional constraint	o/e 0.06	constrained · MANE · 35 bp · p 0.00012 · regional, not allelic
Overall
CADD	27.3	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: TRAF7
Protein: p.Leu640Pro
Coding: c.1919T>C
MANE Select: NM_032271
dbSNP: rs2141299157
Type: single nucleotide variant
Location: chr16:2176305 (GRCh38)
Gene constraint: LOEUF 0.675 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 80.16 · 1 PDB

Full TRAF7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiac, facial, and digital anomalies with developmental delay

Similar variants

TRAF7 p.Arg524Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRAF7 p.Arg655Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRAF7 p.Leu402Val Pathogenic ★★ ⚠ same condition
TRAF7 p.Ser558Phe Pathogenic ★★ ⚠ same condition
TRAF7 p.Ser629Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
TRAF7 p.Arg371Trp Uncertain significance ★★ ⚠ same condition
TRAF7 p.Val554Ile Uncertain significance ★★ ⚠ same condition
TRAF7 p.Arg653Leu 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/traf7-p-leu640pro (accessed [today's date]).

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