Is TWF2 p.Arg235Cys (c.703C>T) pathogenic?

TWF2 p.Arg235Cys (c.703C>T) is classified Uncertain significance in TWF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: ambiguous (0.3991); Very rare (popmax 0.00167%, amr).

How common is TWF2 p.Arg235Cys (c.703C>T) in the general population?

TWF2 p.Arg235Cys (c.703C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TWF2 p.Arg235Cys (c.703C>T)?

AlphaMissense predicts ambiguous (score 0.3991) — an in-silico prediction, not a clinical call.

TWF2 p.Arg235Cys

c.703C>T · VCV3976221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3991	ambiguous
REVEL	0.717	pathogenic-leaning
SaProt	LLR -12.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 9,979 bp · p 0.033 · regional, not allelic
Overall
CADD	31.0	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 0.00167% Admixed American · 1/59,982 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00118% 19/1,613,018 alleles · very rare exomes 18/1,460,778 · genomes 1/152,240 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,982
European (non-Finnish)	0.00136%	73,750
African / African-American	0.00133%	74,950
South Asian	0.0011%	91,062

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: TWF2
Protein: p.Arg235Cys
Coding: c.703C>T
MANE Select: NM_007284
Type: single nucleotide variant
Location: chr3:52229977 (GRCh38)
Gene constraint: LOEUF 0.525 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 91.41 · 2 PDB
Residue 235: the adf-h 2 domain; a β-strand

Full TWF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TWF2 p.Arg235His Uncertain significance ★ ⚠ same residue
TWF2 p.Ala145Val Uncertain significance ★ ⚠ same type
TWF2 p.Ala18Val Uncertain significance ★ ⚠ same type
TWF2 p.Ala292Thr Uncertain significance ★ ⚠ same type
TWF2 p.Ala87Thr Uncertain significance ★ ⚠ same type
TWF2 p.Arg158Cys Uncertain significance ★ ⚠ same type
TWF2 p.Arg188Trp Uncertain significance ★ ⚠ same type
TWF2 p.Arg209Trp 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/twf2-p-arg235cys (accessed [today's date]).

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