Is NEMF p.Leu415Phe (c.1245G>C) pathogenic?

NEMF p.Leu415Phe (c.1245G>C) is classified Uncertain significance in NEMF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-02). AlphaMissense: likely benign (0.1); Ultra-rare (popmax 0.0176%, mid); Associated with Inborn genetic diseases.

What condition is associated with NEMF p.Leu415Phe (c.1245G>C)?

NEMF p.Leu415Phe (c.1245G>C) is associated with Inborn genetic diseases (ClinVar).

How common is NEMF p.Leu415Phe (c.1245G>C) in the general population?

NEMF p.Leu415Phe (c.1245G>C) is ultra-rare (popmax 0.0176%, mid) (gnomAD).

What do computational predictors say about NEMF p.Leu415Phe (c.1245G>C)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

NEMF p.Leu415Phe

c.1245G>C · rs985916082 · VCV2207965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.19	GERP -3.4, phastCons 0.47
Regional constraint	o/e 0.92	unconstrained · MANE · 38 kb · p 0.049 · regional, not allelic
Overall
CADD	17.02	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% Middle Eastern · 1/5,684 alleles

Filtering AF 0.000562% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000975% 15/1,538,726 alleles · ultra-rare exomes 15/1,386,488 · genomes 0/152,238 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0176%	5,684
East Asian	0.00227%	43,960
African / African-American	0.00139%	71,906
European (non-Finnish)	0.00105%	94,939

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: NEMF
Protein: p.Leu415Phe
Coding: c.1245G>C
MANE Select: NM_004713
dbSNP: rs985916082
Type: single nucleotide variant
Location: chr14:49828795 (GRCh38)
Gene constraint: LOEUF 0.687 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.96 · 2 PDB

Full NEMF 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

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NEMF p.Ser785Pro Uncertain significance ★★ ⚠ same condition
NEMF p.Ala12Val Uncertain significance ★ ⚠ same condition
NEMF p.Ala142Val Uncertain significance ★ ⚠ same condition
NEMF p.Ala15Val Uncertain significance ★ ⚠ same condition
NEMF p.Ala295Val 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/nemf-p-leu415phe (accessed [today's date]).

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