Is NXT2 p.Ala35Ser (c.103G>T) pathogenic?

NXT2 p.Ala35Ser (c.103G>T) is classified Uncertain significance in NXT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.0139%, nfe); Associated with male infertility.

What condition is associated with NXT2 p.Ala35Ser (c.103G>T)?

NXT2 p.Ala35Ser (c.103G>T) is associated with male infertility (ClinVar).

How common is NXT2 p.Ala35Ser (c.103G>T) in the general population?

NXT2 p.Ala35Ser (c.103G>T) is ultra-rare (popmax 0.0139%, nfe) (gnomAD).

What do computational predictors say about NXT2 p.Ala35Ser (c.103G>T)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

NXT2 p.Ala35Ser

c.103G>T · rs372211276 · VCV3235105

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0139%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

male infertility

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.76, phastCons 0.99
Regional constraint	o/e 0.48	unconstrained · MANE · 5,678 bp · p 1.8e-07 · regional, not allelic
Overall
CADD	19.5	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 0.0139% European (non-Finnish) · 121/873,411 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0108% 127/1,176,213 alleles · ultra-rare exomes 121/1,064,782 · genomes 6/111,431 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0139%	7,218
Remaining individualsnot grpmax-eligible	0.00868%	11,524
African / African-American	0.00356%	28,123

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: NXT2
Protein: p.Ala35Ser
Coding: c.103G>T
MANE Select: NM_001242617
dbSNP: rs372211276
Type: single nucleotide variant
Location: chrX:109541475 (GRCh38)
Structure: AlphaFold pLDDT 94.35
Residue 35: the ntf2 domain

Full NXT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

male infertility — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NXT2 p.Asp64Ter Likely pathogenic ★ same condition
NXT2 p.Ala118Ser Uncertain significance ★ ⚠ same type
NXT2 p.Ser20Cys Uncertain significance ★ same type
NXT2 p.Gly15Arg Likely benign ★ same type
NXT2 p.Asn124Ser Likely benign 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/nxt2-p-ala35ser (accessed [today's date]).

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