Is NHERF1 p.Pro44Ala (c.130C>G) pathogenic?

NHERF1 p.Pro44Ala (c.130C>G) is classified Conflicting classifications of pathogenicity in NHERF1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-03). AlphaMissense: likely benign (0.0704); Rare (popmax 0.279%, afr); Associated with Inborn genetic diseases.

What condition is associated with NHERF1 p.Pro44Ala (c.130C>G)?

NHERF1 p.Pro44Ala (c.130C>G) is associated with Inborn genetic diseases (ClinVar).

How common is NHERF1 p.Pro44Ala (c.130C>G) in the general population?

NHERF1 p.Pro44Ala (c.130C>G) is rare (popmax 0.279%, afr) (gnomAD).

What do computational predictors say about NHERF1 p.Pro44Ala (c.130C>G)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

NHERF1 p.Pro44Ala

c.130C>G · rs35738271 · VCV1644265

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.279%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -8.10	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 1.3	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 20 kb · p 0.15 · regional, not allelic
Overall
CADD	19.28	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 0.279% African / African-American · 209/74,986 alleles

Filtering AF 0.248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.236%

Overall 0.015% 241/1,607,066 alleles · rare exomes 123/1,454,840 · genomes 118/152,226 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.279%	359
Admixed American	0.0302%	3,309
Remaining individualsnot grpmax-eligible	0.0112%	8,895
South Asian	0.00442%	22,607
European (non-Finnish)	0.000255%	392,847

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: NHERF1
Protein: p.Pro44Ala
Coding: c.130C>G
MANE Select: NM_004252
dbSNP: rs35738271
Type: single nucleotide variant
Location: chr17:74748976 (GRCh38)
Structure: AlphaFold pLDDT 73.02 · 22 PDB
Residue 44: the pdz 1 domain

Full NHERF1 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

NHERF1 p.Pro44= Likely benign ★ same residue
NHERF1 p.Ala120Val Uncertain significance ★★ ⚠ same condition
NHERF1 p.Ala81Val Uncertain significance ★★ ⚠ same condition
NHERF1 p.Arg151Trp Uncertain significance ★★ same condition
NHERF1 p.Arg153Trp Uncertain significance ★★ ⚠ same condition
NHERF1 p.Arg194Gln Uncertain significance ★★ ⚠ same condition
NHERF1 p.Arg198His Uncertain significance ★★ same condition
NHERF1 p.Arg270Cys 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/nherf1-p-pro44ala (accessed [today's date]).

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