Is NOM1 p.Gln685Pro (c.2054A>C) pathogenic?

NOM1 p.Gln685Pro (c.2054A>C) is classified Uncertain significance in NOM1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.3709); Very rare (popmax 0.00271%, nfe).

How common is NOM1 p.Gln685Pro (c.2054A>C) in the general population?

NOM1 p.Gln685Pro (c.2054A>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about NOM1 p.Gln685Pro (c.2054A>C)?

AlphaMissense predicts ambiguous (score 0.3709) — an in-silico prediction, not a clinical call.

NOM1 p.Gln685Pro

c.2054A>C · VCV4121355

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3709 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3709	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 20 kb · p 0.0051 · regional, not allelic
Overall
CADD	26.9	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 0.00271% European (non-Finnish) · 32/1,180,048 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00229% 37/1,614,018 alleles · very rare exomes 35/1,461,754 · genomes 2/152,264 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,830
European (non-Finnish)grpmax	0.00271%	36,877
African / African-American	0.00267%	37,474

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NOM1
Protein: p.Gln685Pro
Coding: c.2054A>C
MANE Select: NM_138400
Type: single nucleotide variant
Location: chr7:156966290 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.73
Residue 685: the mi domain

Full NOM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOM1 p.Ala102Val Uncertain significance ★ ⚠ same type
NOM1 p.Ala133Val Uncertain significance ★ ⚠ same type
NOM1 p.Ala156Val Uncertain significance ★ ⚠ same type
NOM1 p.Ala164Thr Uncertain significance ★ ⚠ same type
NOM1 p.Ala166Val Uncertain significance ★ ⚠ same type
NOM1 p.Ala168Thr Uncertain significance ★ ⚠ same type
NOM1 p.Ala170Thr Uncertain significance ★ ⚠ same type
NOM1 p.Ala273Gly 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/nom1-p-gln685pro (accessed [today's date]).

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