Is DNAI7 p.Leu648Phe (c.1942C>T) pathogenic?

DNAI7 p.Leu648Phe (c.1942C>T) is classified Uncertain significance in DNAI7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.2044); Ultra-rare (popmax 0.0102%, amr).

How common is DNAI7 p.Leu648Phe (c.1942C>T) in the general population?

DNAI7 p.Leu648Phe (c.1942C>T) is ultra-rare (popmax 0.0102%, amr) (gnomAD).

What do computational predictors say about DNAI7 p.Leu648Phe (c.1942C>T)?

AlphaMissense predicts likely benign (score 0.2044) — an in-silico prediction, not a clinical call.

DNAI7 p.Leu648Phe

c.1942C>T · VCV4242990

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2044 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2044	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -0.23, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 87 kb · p 0.044 · regional, not allelic
Overall
CADD	19.57	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 and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L642F vs ClinVar L648F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0102% Admixed American · 5/48,862 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00257%

Overall 0.000648% 9/1,388,486 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0102%	9,772
East Asian	0.0036%	27,792
African / African-American	0.00159%	62,900
European (non-Finnish)	0.000193%	518,737

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: DNAI7
Protein: p.Leu648Phe
Coding: c.1942C>T
MANE Select: NM_018272
Type: single nucleotide variant
Location: chr12:25108775 (GRCh38)
Gene constraint: LOEUF 1.282 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01 · 1 PDB

Full DNAI7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAI7 c.300+1G>A Uncertain significance ★ same type
DNAI7 p.Ala570Thr Uncertain significance ★ ⚠ same type
DNAI7 p.Ala65Thr Uncertain significance ★ ⚠ same type
DNAI7 p.Arg235Gly Uncertain significance ★ ⚠ same type
DNAI7 p.Arg311Gly Uncertain significance ★ ⚠ same type
DNAI7 p.Arg348Gln Uncertain significance ★ ⚠ same type
DNAI7 p.Arg39Cys Uncertain significance ★ ⚠ same type
DNAI7 p.Arg54Gln Uncertain significance ★ ⚠ same type

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/dnai7-p-leu648phe (accessed [today's date]).

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